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EP3886892A1 - Composés foldamères de peptide-oligourée et leurs procédés d'utilisation - Google Patents

Composés foldamères de peptide-oligourée et leurs procédés d'utilisation

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Publication number
EP3886892A1
EP3886892A1 EP19791170.4A EP19791170A EP3886892A1 EP 3886892 A1 EP3886892 A1 EP 3886892A1 EP 19791170 A EP19791170 A EP 19791170A EP 3886892 A1 EP3886892 A1 EP 3886892A1
Authority
EP
European Patent Office
Prior art keywords
amino acid
alkyl
peptide
substituted
disease
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP19791170.4A
Other languages
German (de)
English (en)
Inventor
Robert H. Zimmer
Gilles Guichard
Juliette FREMAUX
Sebastien Goudreau
Claire Venin
Laura Mauran
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ureka Sarl
Original Assignee
Ureka Sarl
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US16/206,433 external-priority patent/US20190142905A1/en
Application filed by Ureka Sarl filed Critical Ureka Sarl
Publication of EP3886892A1 publication Critical patent/EP3886892A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/26—Glucagons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Definitions

  • the present description relates to peptide-based compounds, their synthesis, and use for treating diseases or disorders.
  • the description provides compounds comprising a polypeptide portion, e.g., a-amino acid polypeptide, including or linked to a urea residue or multiple non-consecutive urea residues (e.g., amino acids having an N, N'-linked urea bridging unit).
  • Proteins and peptides are capable of adopting compact, well-ordered conformations, and performing complex chemical operations, e.g., catalysis, highly selective recognition, etc.
  • the three dimensional structure is the principal determinant that governs specificity in protein-protein and/or protein-substrate interactions.
  • the conformation of peptides and proteins is central for their biological function, pharmaceutical efficacy, and their therapeutic preparation.
  • Protein folding is inextricably linked to function in both proteins and peptides because the creation of an "active site" requires proper positioning of reactive groups. Consequently, there has been a long-felt need to identify synthetic polymer or oligomers, which display discrete and predictable (i.e., stable) folding and oligomerizing propensities (hereinafter referred to as "foldamers”) to mimic natural biological systems.
  • PK pharmacokinetic
  • PD pharmacodynamics
  • foldamers stems in part from their resistance to enzymatic degradation. They are also interesting molecules because of their conformational behavior.
  • the elucidation of foldamers having discrete conformational propensities akin to those of natural proteins has led to explorations of peptides constructed from b-, y-, or d-amino acids.
  • both the 3 u and 2.5i 2 helical backbones have been found suitable for the design of stabilized helical peptides useful for therapeutic purposes.
  • amphiphilic 3 14 - helical b-peptides have been constructed from hydrophobic-cationic-hydrophobic- or hydrophobic- hydrophobic-cationic residue triads.
  • a-peptide/modified or peptidomimetic compounds i.e., compounds having a natural or alpha amino acid (poly)peptide having at least one urea amino acid substitution has enhanced or improved properties relative to the parental or cognate "natural" peptide.
  • the description provides peptide compounds or foldamers comprising a portion or sequence of alpha amino acids (i.e., an "a- peptide") including an urea amino acid residue, e.g., a 1,2-ethylene diamine residue having an N,N'- linked urea bridging unit, and including compounds or foldamers having a plurality of non- consecutive urea amino acid residue substitutions, e.g., a 1,2-ethylene diamine residue having an N,N'-linked urea bridging unit.
  • the description provides peptide compounds or foldamers comprising a portion or sequence of alpha amino acids (i.e., an "a-peptide") that includes at least one (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, or 10) residue having a urea, thiourea, or guanidine moiety, e.g., a 1,2-ethylene diamine residue, resulting in an N,N'-linked urea, thiourea, or guanidine bridging unit, respectively.
  • a-peptide a portion or sequence of alpha amino acids
  • a-peptide that includes at least one (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, or 10) residue having a urea, thiourea, or guanidine moiety, e.g., a 1,2-ethylene diamine residue, resulting in an N,N'-linked urea, thiourea, or guanidine bridging unit, respectively.
  • the description also provides for a compound having a plurality (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, or 10) non-consecutive residues having a urea, thiourea, or a quinidine moiety, e.g., a 1,2-ethylene diamine residue, resulting in an N,N'-linked urea, thiourea, or guanidine bridging unit, respectively.
  • the present description provides a-peptide/oligourea compounds, methods of making, and using the same.
  • Amino acid ureas, thioureas, and guanidines represent interesting classes of peptidomimetic foldamers that have previously received little attention.
  • the compounds as described herein improve at least one pharmacokinetic (PK) and/or pharmacodynamics (PD) characteristics of the natural peptide.
  • PK pharmacokinetic
  • PD pharmacodynamics
  • the compounds as described herein can adopt desired secondary structures similar to native peptides, including, e.g., linear, cyclic or helicoidal structures, they can serve as, for example, receptor ligands, effector molecules, agonists, antagonists, modulators of protein-protein interactions, orga nocatalysts or enzymes.
  • An aspect of the present disclosure provides a method of treating, preventing, or ameliorating at least one symptom of a disease or disorder in a subject, the method comprising administering a composition comprising an effective amount of a chimeric compound or foldamer to a subject in need thereof, wherein the composition is effective for treating, preventing, or ameliorating at least one symptom of the disease or disorder and the chimeric compound or foldamer is a GLP-1 analogue having at least one (e.g., a plurality of) amino acid of the compound or foldamer substituted with a residue selected from an aminourea, an aminothiourea, and an aminoguanidine, wherein the disease or disorder is selected from the group consisting of diabetes, obesity, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), a neurodegenerative or cognitive disease or disorder, heart disease, microvascular disease, atherosclerosis or cardiovascular disease, myocardial infarction, strokes, or a combination thereof
  • An aspect of the present disclosure provides a method of treating, preventing, or ameliorating at least one symptom of, a disease or disorder in a subject, the method comprising administering a composition comprising an effective amount of a chimeric compound or foldamer to a subject in need thereof, wherein the chimeric compound or foldamer is a GLP-1 analogue having at least one amino acid substituted with a residue having a urea, a thiourea, or a guanidine moiety resulting in an N, N'-linked urea, thiourea, or guanidine bridging unit, respectively, wherein the disease or disorder is selected from the group consisting of diabetes, obesity, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), a neurodegenerative or cognitive disease or disorder, heart disease, microvascular disease, atherosclerosis or cardiovascular disease, myocardial infarction, strokes, or a combination thereof, and wherein the composition is
  • the GLP-1 analogue is selected from the group consisting of lixisenatide, exenatide, semaglutide, liraglutide, albiglutide, dulaglutide, derivatives thereof, and combinations thereof.
  • an amino acid of the chimeric compound or foldamer is an amino acid modified with a fatty acid glutamate (e.g., palmitoyl glutamate).
  • a fatty acid glutamate e.g., palmitoyl glutamate
  • the neurodegenerative or cognitive disease or disorder includes peripheral neuropathy, multiple system atrophy, chronic traumatic encephalopathy (CTE), spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), vascular dementia, dementia with Lewy bodies (DLB), frontotemporal dementia, Creutzfeldt-Jakob disease, idiopathic normal pressure hydrocephalus, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic sclerosis, multiple sclerosis, traumatic brain injury, spinal cord injury, or a combination thereof.
  • CTE chronic traumatic encephalopathy
  • SCA spinocerebellar ataxia
  • SMA spinal muscular atrophy
  • vascular dementia dementia with Lewy bodies
  • DLB dementia with Lewy bodies
  • Creutzfeldt-Jakob disease Creutzfeldt-Jakob disease
  • idiopathic normal pressure hydrocephalus Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic sclerosis, multiple
  • the composition further comprises a pharmaceutically acceptable carrier or excipient.
  • At least one amino acid side chain is modified with a fatty acid glutamic acid.
  • At least one amino acid side chain is modified with a palmitoyl glutamic acid
  • the substituted amino acid is located in the first 4 amino acids (N-terminal) of the peptide.
  • the substituted amino acid is located at or within 3 amino acids of an amino acid that is key for the interaction between the protein and a receptor, ligand or other polypeptide that interacts with the peptide.
  • the substituted amino acid is located at or within 3 amino acids of an amino acid that is key for at least one pharmacokinetic property of the peptide.
  • the substituted amino acid is located at or within 3 amino acids of an amino acid that is key for at least one physical property of the peptide.
  • the substitution is an N,N' linked substitution.
  • the residue having the urea, the thiourea, the guanidine are independently selected from the group consisting of:
  • X is independently selected from the group consisting of 0, S, NH;
  • R is independently selected from the group consisting of hydrogen, any side chain of a natural amino acid, linear, branched or cyclic Cl-C6-alkyl, alkenyl or alkynyl; mono- or -bicyclic aryl, mono or bicyclic heteroaryl having up to five heteroatoms selected from N, O and S; mono or bicyclic a ryl-Cl-C6-a Ikyl, alkenyl or alkynyl; Cl- C6-alkyloxy, aryloxy, heteroaryloxy, thio, Cl-C6-a Ikylthio, amino, mono ordi-Cl-C6- alkylamino, carboxylic acid, carboxamide mono- or di-Cl-C6-alkylcarboxamine, sulfonamide, urea, mono-di or tri-substituted urea, thiourea, guanidine;
  • R 1 is independently selected from the group consisting of hydrogen, linear,
  • R 2 is independently selected from the group consisting of hydrogen, linear, branched or cyclic Cl-C6-alkyl, alkenyl or alkynyl; mono- or -bicyclic aryl, mono or bicyclic heteroaryl having up to five heteroatoms selected from N, 0 and S;
  • the chimeric compound or foldamer includes the amino acid sequence of SEQ ID NO: 15.
  • the chimeric includes an amino acid modified with a fatty acid glutamate.
  • the chimeric compound or foldamer is compound 77.
  • the description provides peptide-oligourea compounds that comprise at least one substitution of an a-amino acid of the parent peptide sequence with an urea amino acid residue.
  • the compound comprises a plurality of substitutions.
  • the plurality of subsititutions includes at least one on-consecutive, monosubstitution.
  • the oligourea residue is substituted with an identical or homologous (i.e., conservative change) proteinogenic amino acid side chain.
  • the method further comprises co administer an farnesoid X receptor (FXR) agonist.
  • FXR farnesoid X receptor
  • the FXR agonist is selected from cafestol, chenodeoxycholic acid, obeticholic acid, fexaramine, or a combination thereof.
  • the description provides peptide-oligourea compounds in which a plurality of non-consecutive a-amino acids of the parent peptide sequence are substituted with a urea amino acid residue.
  • the description provides peptide-oligourea compound (e.g. a foldamer) comprising a plurality of amino acids substitution with a residue selected from an urea (e.g., substituted or unsubstituted N-2-aminoethylcarbamoyl residue), a thiourea (e.g., substitute or unsubstituted N-(2-aminoethyl)carbamothioyl), and a guanidine (e.g., substitute or unsubstituted N-(2-aminoethyl)formamidinyl), wherein at least one non-consecutive amino acid has been monosubstituted by an aminourea, a thiourea, or a guanidine.
  • an urea e.g., substituted or unsubstituted N-2-aminoethylcarbamoyl residue
  • a thiourea e.g., substitute
  • the substitution or substitutes can be located anywhere within the parental polypeptide or peptidomimetic chain.
  • the urea amino acid residue or residues are coupled, joined to or contiguous with the a-peptide amino acid backbone.
  • the urea amino acid residues are "fused" to a terminus, e.g., amino terminus, carboxy terminus or both, of the peptide (e.g., an a-amino acid peptide) or peptidomimetic.
  • the urea amino acid residues are substituted with an identical or homologous (i.e., conservative change) proteinogenic amino acid side chain.
  • the substituted residue e.g., the monosubstituted amino acid
  • the substituted residue is located in the first 4 amino acids (N-terminal) of the peptide or peptidomimetic.
  • the substituted residue is located in the last 4 amino acids (C-terminal) of the peptide or peptidomimetic.
  • the substituted residue e.g., the monosubstituted amino acid
  • the substituted residue is located at or within 3 amino acids of a peptidase degradation site of the peptide or peptidomimetic.
  • the substituted residue e.g., the monosubstituted amino acid
  • the substituted residue is located at or within 3 amino acids of an amino acid that is key for the interaction between the protein and a receptor or protein that interacts with the natural/parent/native/unmodified protein.
  • the substituted residue e.g., the monosubstituted amino acid
  • the substituted residue is located at or within 3 amino acids of an amino acid that is key for at least one pharmacokinetic property of the protein.
  • the substituted residue e.g., the monosubstituted amino acid
  • the substituted residue is located at or within 3 amino acids of an amino acid that is key for at least one physical or biological property of the protein.
  • the substituted residue e.g., the monosubstituted amino acid
  • 3 or more amino acids have been substituted with a residue
  • the peptide or peptidomimetic is 4 or more (e.g., 5, 6, 7, 8, 9, 10, or more) amino acids.
  • the peptide or peptidomimetic is a class B GPCR ligand or derivative thereof, such as lixisenatide, exenatide, semaglutide, liraglutide, albiglutide, dulaglutide, derivatives thereof, or combinations thereof.
  • the substation residue of the compound comprises a peptidomimetic urea residue, for example, a 1, 2-ethylene diamine residue having an N, N'-linked urea bridging unit.
  • the compound comprises at least one other modified or peptidomimetic amino acid residue, such as, an amino acid analog, e.g., one or more y-amino acid residue, as well as other members of the y-peptide superfamily including y-peptides and oligocarbamates or a combination thereof.
  • the at least one other modified or peptidomimetic amino acid residue is a N-( 2- aminoethyl)carbamoyl residue, a substituted or unsubstituted N-(2-aminoethyl)carbamothioyl residue, a substituted or unsubstituted N-(2-aminoethyl)formamidinyl residue, a substituted or unsubstituted 2-aminoethanoxycarbonyl residue or a combination or oligomer thereof.
  • the peptide-oligourea comprises at least two non-consecutive modified or peptidomimetic amino acid residues having an N, N'-linked urea bridging unit.
  • at least one of the modified or pseudoamino acid residues is a / ⁇ /-(2-aminoethyl)carbamoyl residue, a substituted or unsubstituted N-(2-aminoethyl)carbamothioyl residues, a substituted or unsubstituted N-(2- aminoethyl)formamidinyl residues, a substituted or unsubstituted 2-aminoethanoxycarbonyl residue or a combination thereof.
  • the description provides urea amino acid-containing peptides that adopt stable secondary structures, including, e.g., linear, cyclic, or helicoidal, tertiary structure, and/or quaternary structures.
  • the urea amino acid (i.e., peptidomimetic residue) includes a substituted or unsubstituted / ⁇ /-2-aminoethylcarbamoyl residue a y-amino acid residue, a substituted and unsubstituted N-(2-aminoethyl)carbamothioyl residues, a substituted and unsubstituted N-(2-aminoethyl)formamidinyl residues, and a substituted and unsubstituted 2- aminoethanoxycarbonyl residues.
  • the peptide comprises two or more non-consecutive peptidomimetic residues.
  • the urea amino acid is substituted with a proteinogenic amino acid side chain.
  • the description provides compounds, as described herein, that are capable of binding specifically to a target, e.g., a protein such as a receptor, ligand or other polypeptide or peptide, or small molecule, similar to the native/natural/parent/unmodified peptide.
  • a target e.g., a protein such as a receptor, ligand or other polypeptide or peptide, or small molecule, similar to the native/natural/parent/unmodified peptide.
  • the peptide-oligourea ligand compound comprises a peptide that includes a plurality of N, N'-linked urea / ⁇ /-2-aminoethyl residues as y-amino acid residue analogues, wherein at least one of the residues is a non-consecutive, monosubstitution.
  • the peptide comprises a-amino acids.
  • the peptide-oligourea ligand compound comprises an amino acid sequence contiguous with or coupled to one or more oligourea peptidomimetic residues, wherein the peptidomimetic residue is selected from the group consisting of substituted and unsubstituted / ⁇ /-2-aminoethylcarbamoyl residue, as well as isosteric residus, such as y-amino acid residues, substituted and unsubstituted N-(2-aminoethyl)carbamothioyl residues, substituted and unsubstituted N-(2-aminoethyl)formamidinyl residues, and substituted and unsubstituted 2-aminoethanoxycarbonyl residues, and a combination thereof.
  • the peptide-oligourea ligand compound comprises two or more urea peptidomimetic residues. , wherein at least one urea peptidomimetic residue is not adjacent to another urea peptidomimetic residue (i.e., at least one peptidomimetic residue is non-consecutive with another peptidomimetic residue).
  • the urea amino acid or urea peptidomimetic residue comprises an acyclic y-amino acid residue. In additional embodiments, the urea amino acid or urea peptidomimetic residue comprises an / ⁇ /-(2-aminoethyl)carbamoyl residue, acyclic y-amino acid residue or a combination thereof.
  • the urea amino acid or urea peptidomimetic residue comprises an isosteric residue such as y-amino acid residue, substituted or unsubstituted N-(2-aminoethyl)carbamothioyl residue, substituted or unsubstituted N-(2-aminoethyl)formamidinyl residue, substituted or unsubstituted 2- aminoethanoxycarbonyl residue or a combination thereof.
  • the description provides compounds comprising a peptide comprising at least one (e.g., at least 2, 3, or 4) non-consecutive urea amino acid or urea peptidomimetic residue comprising a N, N'-linked urea 1,2-ethylene diamine residue.
  • the urea amino acid includes a peptidomimetic 1,2-ethylene diamine residue with N, N'-linked urea bridging unit.
  • the peptidomimetic residue is a substituted or unsubstituted N- 2- aminoethylcarbamoyl residue.
  • the compounds polypeptide includes at least one a-, y-, d- amino acid, derivative or combination thereof, which is contiguous with or coupled to one or multiple (e.g., at least 1, 2, 3, 4, 5, or 6) non-consecutive peptidomimetic 1,2-ethylene diamine residues having an N, N'-linked urea bridging unit.
  • the peptide compound comprises a substituted or unsubstituted N-(2-aminoethyl)carbamoyl residue.
  • the compound comprises at least one non- consecutive urea amino acid or peptidomimetic residue (e.g., a monosubstituted urea amino acid or peptidomimetic residue) contiguous with or covalently linked or joined to at least one of the amino terminus (N'), the carboxyl terminus (C'), within the peptide sequence or a combination thereof.
  • the compound comprises a plurality of urea amino acids or peptidomimetic residues.
  • the compound comprises 1, 2, 3, 4, 5, 6, 1 , 8, 9, 10, 11, 12, 13, 14, 15, 16 ,17, 18 ,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38 ,39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63 ,64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78 ,79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89,
  • the residue is at least one of a y-amino acid residue, substituted or unsubstituted N-(2-aminoethyl)carbamothioyl residue, substituted or unsubstituted N-(2- aminoethyl)formamidinyl residue, substituted or unsubstituted 2-aminoethanoxycarbonyl residue or combination thereof.
  • the urea amino acid is an substituted or unsubstited N-(2-aminoethyl)carbamoyl residue.
  • the aminoethylcarbamoyl residue is substituted with a proteinogenic amino acid side chain.
  • the compounds can further comprise at least one additional chemical modification.
  • the chemical modification includes at least one of, for example, acetylation, phosphorylation, methylation, glycosylation, prenylation, isoprenylation, farnesylation, geranylation, pegylation, a disulfide bond, or combination thereof.
  • the description provides pharmaceutically acceptable acid and base salt forms of the peptide-oligourea compounds described herein.
  • the foldamers as described herein including pharmaceutically acceptable salts thereof are useful for the preparation of a medicament and/or the treatment of disease in a subject.
  • the compounds of the present disclosure may optionally be administered with at least one of a pharmaceutically acceptable excipient or carrier, pharmacologically active agent or a combination thereof.
  • a pharmaceutically acceptable carrier or excipient comprising an effective amount of a compound as described herein, and a pharmaceutically acceptable carrier or excipient.
  • the description also provides methods of treating a disease or disorder or ameliorating the effects of the same comprising the steps of administering to an individual in need thereof, a composition comprising an effective amount of a compound or salt form thereof as described herein, and a pharmaceutically acceptable carrier or excipient, wherein the composition is effective for treating, preventing or ameliorating the effects of the disease or disorder.
  • the disease or disorder is selected from the group consisting of diabetes (such as diabetes mellitus type 1 or diabetes mellitus type 2), a neurodegenerative disease or disorder (such as peripheral neuropathy, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic sclerosis, multiple sclerosis, traumatic brain injury, or spinal cord injury), or a combination thereof.
  • diabetes such as diabetes mellitus type 1 or diabetes mellitus type 2
  • a neurodegenerative disease or disorder such as peripheral neuropathy, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic sclerosis, multiple sclerosis, traumatic brain injury, or spinal cord injury
  • the present description provides methods of making and using the compounds as described herein.
  • the compounds as described herein can be used as a diagnostic agent or a therapeutic agent for the treatment of a disease or condition.
  • the present description provides methods of making compounds as described herein.
  • the present description provides for the synthesis of non natural amino acids substituted by a wide range of functional R groups including proteinogenic side chains.
  • the description provides compounds, which comprise non-natural oligourea amino acids (i.e., an amino acid having an N, N'-linked urea bridging unit) and/or peptoid versions of the same together with natural amino acids, wherein the modified peptides or foldamers form functional biopolymers.
  • the present description provides a method of improving at least one biological property, such as therapeutic effect, of a peptide or a peptidomimetic, the method comprising: substituting a plurality of amino acids of the peptide or peptidomimetic with a residue selected from an aminourea, a thiourea, and a guanidine, wherein at least one non-consecutive amino acid has been monosubstituted by an aminourea, a thiourea, or a guanidine.
  • Figures 1A and IB Covalent structure of an exemplary oligourea monomer (top) within a N,N'- linked oligourea (bottom). Backbone dihedral angles are marked by curved arrows. R denotes any proteinogenic amino acid side chain.
  • B Formula and X-ray structure (right) of oligourea hexamer 1 and antibacterial oligourea octamer 1A.
  • Figures 3A, 3B, and 3C Comparison of exemplary peptide foldamers as described herein with exenatide.
  • Figure 3A shows the effect on blood glucose before and after IV treatment.
  • Figure 3B shows the effect on blood glucose before and after glucose load.
  • Figure 3C shows the area under the curve (AUC) for the same.
  • Figures 4A, 4B, and 4C Comparison of exemplary peptide foldamers as described herein with lixisenatide.
  • Figure 4A shows the effect on blood glucose before and after IV treatment.
  • Figure 4B shows the effect on blood glucose before and after glucose load.
  • Figure 4C shows the area under the curve (AUC) for the same.
  • Figure 7 Comparison of exemplary foldamers as described herein with exenatide. Several of the exemplary peptide foldamers as described herein demonstrate superior ability to reduce glucose.
  • Figures 8A, 8B, 8C, 8D, 8E, 8F, and 8G Figure 8A illustrates compound 77, Figure 8B illustrates compound 78, Figure 8C illustrates compound 79, Figure 8D illustrates compound 80, Figure 8E illustrates compound 81, Figure 8F illustrates compound 82, and Figure 8G illustrates compound 83.
  • Figure 9 Illustrate the chemical structure of a urea, a g-amino acid, and a N,N'-linked carbomyl.
  • an amino acid abbreviation followed with a superscript "u” represents a urea substitution with the specified amino acid side chain (e.g., as shown in Figure 9, A u represents a urea substitution with an alanine side chain); an amino acid abbreviation followed with a superscript "c” represented a N,N'-linked carbomyl with the specified amino acid side chain (e.g., as shown in Figure 9, A c represents an N,N' linked carbomyl with an alanine side chain); and "g" followed by an amino acid abbreviation represents a g-amino acid of the specified amino acid (e.g., gA represents a g alanine).
  • FIGS 10A, 10B, and IOC Flypoglycemic effects of exemplary GLP-1 analogue compound 77.
  • A Blood glucose evolution after vehicle (circle) or compound 77 (triangle) injection (two-way ANOVA and Bonferroni post-test: *** p ⁇ 0,001).
  • B Blood glucose during an intra peritoneal glucose tolerance test at day 4 post-treatment with vehicle (circule) or compound 77 (triangle; two-way ANOVA and Bonferroni post-test: ** p ⁇ 0,01; *** p ⁇ 0,001).
  • C AUC of the ipGTT (Student t-test: ** p ⁇ 0,01).
  • Figures 11A, 11B, 11C, and 11C are examples of the ipGTT.
  • Exemplary compound 77 limits body weight and decrease liver damage markers.
  • A Absolute body weight during the treatment period (two-way Anova and Bonferroni post-test: * p ⁇ 0,05; ** p ⁇ 0.01).
  • B Liver weight relative to body weight (One-way Anova with Dunnett's Multiple Comparison Test: *** p ⁇ 0.001).
  • C and D Plasma ALT and AST during the treatment period. (Kruskal-Wallis with Dunn's multiple comparison test: *p ⁇ 0,05; ** p ⁇ 0.01).
  • FIGS 12A, 12B, and 12C Compound 77 and obeticholic acid tend to reduce liver lipids: liver total cholesterol (A), triglycerides (B) and fatty acids levels (C).
  • A liver total cholesterol
  • B triglycerides
  • C fatty acids levels
  • FIGs 13A and 13B Compound 77 reduces more efficiently the NAS-score than OCA.
  • B NAS-score (One-way Anova with Dunnett's Multiple Comparison Test: *p ⁇ 0,05; ** p ⁇ 0.01).
  • Figures 12A, 14B, and 14C Inflammatory and fibrosis marker are reduced by compound 77 and OCA. Relative mRNA expression of inflammatory (A), fibrosis (B) and ER-stress markers (C). (Kruskal-Wallis with Dunn's Multiple Comparison Test: *p ⁇ 0,05; ** p ⁇ 0.01).
  • FIGs 15A, 15B, and 15C Compound 77 shows anti-diabetic properties, but not OCA. Fasted blood glucose (A), plasma insulin (B) and HOMA-IR index (C) during the treatment period. (Kruskal-Wallis with Dunn's multiple comparison test: * p ⁇ 0,05; ** p ⁇ 0,01; *** p ⁇ 0,001).
  • Figure 17 Stability of Compound 77 in mouse plasma.
  • Figure 18 HPLC profile of Compound 77 (10-100%; CH 3 CN 0.1 % TFA in H 2 0 0.1% TFA, 10 min, C18).
  • An aspect of the present disclosure provides a method of treating, preventing, or ameliorating at least one symptom of a disease or disorder in a subject, the method comprising administering a composition comprising an effective amount of a chimeric compound or foldamer to a subject in need thereof, wherein the composition is effective for treating, preventing, or ameliorating at least one symptom of the disease or disorder and the chimeric compound or foldamer is a GLP-1 analogue having at least one amino acid of the compound or foldamer substituted (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 substitutions) with a residue selected from an aminourea, an aminothiourea, and an aminoguanidine, wherein the disease or disorder is selected from the group consisting of diabetes, obesity, non-alcoholic a composition comprising an effective amount of a chimeric compound or foldamer to a subject in need thereof, wherein the composition is effective for treating, preventing, or ameliorating at least one symptom of the disease
  • the present disclosure provides a method of treating, preventing, or ameliorating at least one symptom of, a disease or disorder in a subject, the method comprising administering a composition comprising an effective amount of a chimeric compound or foldamer to a subject in need thereof, wherein the chimeric compound or foldamer is a GLP-1 analogue having at least one amino acid substituted with a residue having a urea, a thiourea, or a guanidine moiety resulting in an N, N'- linked urea, thiourea, or guanidine bridging unit, respectively, wherein the disease or disorder is selected from the group consisting of diabetes, obesity, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), a neurodegenerative or cognitive disease or disorder, heart disease, microvascular disease, atherosclerosis or cardiovascular disease, myocardial infarction, strokes, or a combination thereof, and
  • NAFLD non-alcoholic fatty liver
  • the neurodegenerative or cognitive disease or disorder includes peripheral neuropathy, multiple system atrophy, chronic traumatic encephalopathy (CTE), spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), vascular dementia, dementia with Lewy bodies (DLB), frontotemporal dementia, Creutzfeldt-Jakob disease, idiopathic normal pressure hydrocephalus, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic sclerosis, multiple sclerosis, traumatic brain injury, spinal cord injury, or a combination thereof.
  • CTE chronic traumatic encephalopathy
  • SCA spinocerebellar ataxia
  • SMA spinal muscular atrophy
  • vascular dementia dementia with Lewy bodies
  • DLB dementia with Lewy bodies
  • Creutzfeldt-Jakob disease Creutzfeldt-Jakob disease
  • idiopathic normal pressure hydrocephalus Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic sclerosis, multiple
  • the composition further comprises a pharmaceutically acceptable carrier or excipient.
  • the method further comprises co-administering (as described herein) an farnesoid X receptor (FXR) agonist.
  • the FXR agonist may be selected from cafestol, chenodeoxycholic acid, obeticholic acid, fexaramine, or a combination thereof.
  • the GLP-1 analogue is selected from the group consisting of lixisenatide, exenatide, semaglutide, liraglutide, albiglutide, dulaglutide, derivatives thereof, and combinations thereof.
  • an amino acid of the chimeric compound or foldamer is an amino acid modified with a fatty acid glutamate.
  • a lysine residue may be modified with a fatty acid glutamate.
  • the fatty acid of the fatty acid glutamate may be a C8-C18 fatty acid, such as palmitoyl.
  • an amino acid of the chimeric compound or foldamer is an amino acid modified with a palmitoyl glutamate, such as a lysine.
  • the chimeric compound or foldamer includes the amino acid sequence of SEQ ID NO: 15, which may include an amino acid that has been modified with a fatty acid glutamate.
  • the chimeric compound or foldamer is compound 77.
  • the substitution is an N,N' linked substitution.
  • At least one amino acid sidechain is modified with a fatty acid glutamic acid.
  • At least one amino acid sidechain is modified with a palmitoyl glutamic acid
  • the substituted amino acid is located in the first 4 amino acids (N-terminal) of the peptide.
  • the substituted amino acid is located at or within 3 amino acids of an amino acid that is key for the interaction between the protein and a receptor, ligand or other polypeptide that interacts with the peptide.
  • the substituted amino acid is located at or within 3 amino acids of an amino acid that is key for at least one pharmacokinetic property of the peptide.
  • the substituted amino acid is located at or within 3 amino acids of an amino acid that is key for at least one physical property of the peptide.
  • the residue having the urea, the thiourea, the guanidine are independently selected from the group consisting of:
  • X is independently selected from the group consisting of 0, S, NH;
  • R is independently selected from the group consisting of hydrogen, any side chain of a natural amino acid, linear, branched or cyclic Cl-C6-alkyl, alkenyl or alkynyl; mono- or -bicyclic aryl, mono or bicyclic heteroaryl having up to five heteroatoms selected from N, O and S; mono or bicyclic a ryl-Cl-C6-a Ikyl, alkenyl or alkynyl; Cl- C6-alkyloxy, aryloxy, heteroaryloxy, thio, Cl-C6-a Ikylthio, amino, mono ordi-Cl-C6- alkylamino, carboxylic acid, carboxamide mono- or di-Cl-C6-alkylcarboxamine, sulfonamide, urea, mono-di or tri-substituted urea, thiourea, guanidine;
  • R 1 is independently selected from the group consisting of hydrogen, linear,
  • R 2 is independently selected from the group consisting of hydrogen, linear, branched or cyclic Cl-C6-alkyl, alkenyl or alkynyl; mono- or -bicyclic aryl, mono or bicyclic heteroaryl having up to five heteroatoms selected from N, 0 and S;
  • the description provides peptide-oligourea compounds that comprise at least one substitution (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 113, 14, 15, 16, 17, 18, 19, or 20 substitutions) of an amino acid (e.g., an a-amino acid) of the parent peptide sequence with an oligourea residue (e.g., urea, thiourea, or guanidine).
  • an amino acid e.g., an a-amino acid
  • an oligourea residue e.g., urea, thiourea, or guanidine
  • at least one of the substitutions is a non-consecutive, monosubstitution.
  • the oligourea residue is substituted with an identical or homologous (i.e., conservative change) proteinogenic amino acid side chain.
  • the description provides peptide-oligourea compounds in which oligourea residues replace at least one amino acid in the carboxy terminus, amino terminus, in between the termini, or a combination thereof.
  • the oligourea residues a re coupled, joined to or contiguous with the a-peptide amino acid backbone with at least one of the substitutions being a non-consecutive, monosubstitution.
  • the oligourea residues are "fused" to a terminus, e.g., amino terminus, carboxy terminus or both, of an a-amino acid peptide.
  • the oligourea residues are substituted with an identical or homologous (i.e., conservative change) proteinogenic amino acid side chain.
  • the substitution of an amino acid (e.g., an a-amino acid) of the parent peptide sequence includes at least one monosubstitution of non-consecutive amino acids with an urea residue as described herein (e.g., urea, thiourea, or guanidine).
  • the description provides a peptide-oligourea compound (e.g. a foldamer) comprising a plurality of amino acids substitution with a residue selected from an urea (e.g., substituted or unsubstituted N-2-aminoethylcarbamoyl residue), a thiourea (e.g., substitute or unsubstituted N-(2-aminoethyl)carbamothioyl), and a guanidine (e.g., substitute or unsubstituted N-(2-aminoethyl)formamidinyl), wherein at least one non-consecutive amino acid has been monosubstituted by an aminourea, a thiourea, or a guanidine.
  • an urea e.g., substituted or unsubstituted N-2-aminoethylcarbamoyl residue
  • a thiourea e.g.
  • Aliphatic y-peptides i.e. oligoamides comprising some or all of y-amino acid residues, represent an interesting class of peptidomimetic residues that have received little attention previously. Compared to a-amino acids, y-amino acids are characterized by a greater chemical diversity (seven substitution positions versus three for a-amino acids) and conformational versatility.
  • the y-peptide backbone can be seen as the prototypic member of a larger family (i.e.
  • y- peptide superfamily or lineage of peptidomimetic backbones and combinations thereof, all sha ring an isosteric relationship (e.g.oligocarbamates, N,N'- linked oligo(thio)ureas, oligoguanidines, oligomers of 6-aminoxy acids, sulfonamidopeptides).
  • oligocarbamates N,N'- linked oligo(thio)ureas, oligoguanidines, oligomers of 6-aminoxy acids, sulfonamidopeptides.
  • amide for y-peptide
  • ca rbamate for oligoca rbamates
  • urea for oligourea units
  • oligomers consisting of urea and carbamate or urea and amide linkages arranged in a 1:1 pattern adopt a helical conformation akin to that of urea homoligomers and y- peptide foldamers.
  • helix formation is mainly driven by the presence of the urea units whose propensity for folding surpasses that of amide and carbamate units.
  • a reference to "A and/or B", when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.
  • the phrase "at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from anyone or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements.
  • This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase "at least one" refers, whether related or unrelated to those elements specifically identified.
  • At least one of A and B can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.
  • co-administration and “co-administering” or “combination therapy” refer to both concurrent administration (administration of two or more therapeutic agents at the same time) and time varied administration (administration of one or more therapeutic agents at a time different from that of the administration of an additional therapeutic agent or agents), as long as the therapeutic agents are present in the patient to some extent, preferably at effective amounts, at the same time.
  • one or more of the present compounds described herein are co-administered in combination with at least one additional bioactive agent.
  • the co-administration of compounds results in synergistic activity and/or therapy.
  • Peptides are typically short chains of amino acid monomers linked by peptide (amide) bonds, the covalent chemical bonds formed when the carboxyl group of one amino acid reacts with the amino group of another.
  • the shortest peptides are dipeptides, consisting of 2 amino acids joined by a single peptide bond, followed by tripeptides, tetrapeptides, etc.
  • a polypeptide is a long, continuous, and unbranched peptide chain.
  • amino refers to -NH2 and substituted derivatives thereof wherein one or both of the hydrogens are independently replaced with 20 substituents selected from the group consisting of alkyl, haloalkyl, fluoro alkyl , alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, aralkyl, hetero aryl , hetero aralkyl , alkylcarbonyl, haloalkylcarbonyl, carbocyclylcarbonyl, fluoroalkylcarbonyl, alkenylcarbonyl, heterocyclylcarbonyl, arylcarbonyl, alkynylcarbonyl, aralkylcarbonyl, heteroarylcarbonyl, heteroaralkylcarbonyl and the sulfonyl and sulfinyl groups defined above; or when both hydrogens together are replaced with an alkylene group (to form a ring
  • amino acid refers to any molecule that contains both amino and carboxylic acid functional groups, and includes any of the naturally occurring amino acids (e.g. Ala, Arg, Asn, Asp, Cys, Glu, Gin, Gly, His, Hyl, Hyp, lie, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val) in D, L, or DL form.
  • naturally occurring amino acids e.g. Ala, Arg, Asn, Asp, Cys, Glu, Gin, Gly, His, Hyl, Hyp, lie, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val
  • side chains of naturally occurring amino acids include, for example, hydrogen (e.g., as in glycine), alkyl (e.g., as in alanine, valine, leucine, isoleucine, proline), substituted alkyl (e.g., as in threonine, serine, methionine, cysteine, aspartic acid, asparagine, glutamic acid, glutamine, arginine, and lysine), alkaryl (e.g., as in phenylalanine and tryptophan), substituted arylalkyl (e.g., as in tyrosine), and heteroarylalkyl (e.g., as in histidine).
  • the term is inclusive of various types of amino acids including a-, b-, y-, or d-amino acids, analogs and derivatives of the same, unless the context clearly indicates otherwise.
  • amino acid side chain or “amino acid residue” shall mean, within context, a radical of a D- or L-amino acid side chain (derived from an amino acid) which functions as a substituent on another group, often an alkylene (usually a methylene) group on R2' or R3' as otherwise described herein.
  • Preferred amino acid side chains for use in the present disclosure are derived from the side chains of both natural and unnatural amino acids, preferably including, for example, alanine, b-alanine, arginine, asparagine, aspartic acid, cyclohexylalanine, cysteine, cystine, glutamic acid, glutamine, glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methionine, naphthylalanine, norleucine, norvaline, proline, serine, threonine, valine, tryptophan or tyrosine, among others.
  • natural and unnatural amino acids preferably including, for example, alanine, b-alanine, arginine, asparagine, aspartic acid, cyclohexylalanine, cysteine, cystine, glutamic acid, glutamine, glycine, phenylalanine, histidine, iso
  • any amino acid can mean any natural or synthetic amino acid, including a-, b-, y-, or d-amino acids, possibly modified by the presence of one or more substituents, or combinations thereof, including analogs, derivatives, mimetics, and peptoid versions of the same. More precisely the term a-amino acid means an alpha aminated amino acid with the following general structure:
  • R represents the side chain of the amino acid.
  • R therefore represents the side chain of a side or non-side amino acid.
  • the term "natural amino acid” means any amino acid which is found naturally in vivo in a living being. Natural amino acids therefore include amino acids coded by mRNA incorporated into proteins during translation but also other amino acids found naturally in vivo which are a product or by-product of a metabolic process, such as for example ornithine which is generated by the urea production process by arginase from L-arginine. In the present disclosure, the amino acids used can therefore be natural or not. Namely, natural amino acids generally have the L configuration but also, an amino acid can have the L or D configuration. Moreover, R is of course not limited to the side chains of natural amino acid, but can be freely chosen.
  • urea or carbamide is an organic compound with the chemical formula CO(NH 2 ) 2 .
  • peptide precursor or “parental peptide” refers, but is in no way limited to, a parental a-peptide sequence that is coupled with oligourea pseudopeptide or peptidomimetic subunits or substituting oligourea pseudopeptide subunits (i.e., exchanging one or more a-amino acids for one or more oligourea pseudopeptide subunits).
  • urea amino acid or "urea peptidomimetic” refers, but is in no way limited to, a residue containing N, N'-linked urea residues including oligomers of substituted or unsubstituted N-2-ethylaminocarbamoyl or 1, 2-ethylene diamine residues.
  • compound or “foldamer”, as used herein, unless otherwise indicated, refers to any specific chemical compound disclosed herein and includes tautomers, regioisomers, geometric isomers, and where applicable, stereoisomers, including optical isomers (enantiomers) and other steroisomers (diastereomers) thereof, as well as pharmaceutically acceptable salts and derivatives (including prodrug forms) thereof where applicable, in context.
  • compound generally refers to a single compound, but also may include other compounds such as stereoisomers, regioisomers and/or optical isomers (including racemic mixtures) as well as specific enantiomers or enantiomerically enriched mixtures of disclosed compounds.
  • the term also refers, in context to prodrug forms of compounds which have been modified to facilitate the administration and delivery of compounds to a site of activity. It is noted that in describing the present compounds, numerous substituents and variables associated with same, among others, are described. It is understood by those of ordinary skill that molecules which are described herein are stable compounds as generally described hereunder. When the bond is shown, both a double bond and single bond are represented within the context of the compound shown.
  • hydrocarbyl shall mean a compound which contains carbon and hydrogen and which may be fully saturated, partially unsaturated or aromatic and includes aryl groups, alkyl groups, alkenyl groups and alkynyl groups.
  • amido as used herein means an ammo group, as defined herein, appended to the parent molecular moiety through a carbonyl.
  • nitro as used herein means a -N02 group.
  • zido as used herein means a -N3 group.
  • Me, Et, Ph, Tf, Nf, Ts, Ms, Cbz, and Boc represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, p-toluenesulfonyl, methanesulfonyl, carbobenzyloxy, and tert-butyloxycarbonyl, respectively.
  • Alkyl refers to a branched or unbranched alkyl group having 1-6 carbon atoms, a branched or unbranched alkenyl group having 1-6 carbon atoms, a branched or unbranched alkinyl group having 1-6 carbon atoms.
  • alkyl shall mean within its context a linear, branch- chained or cyclic fully saturated hydrocarbon radical or alkyl group, preferably a C1-C10, more preferably a C1-C6, alternatively a C1-C3 alkyl group, which may be optionally substituted.
  • alkyl groups are methyl, ethyl, n-butyl, sec-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, isopropyl, 2-methylpropyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylethyl, cyclohexylethyl and cyclohexyl, among others.
  • compounds according to the present disclosure may be used to covalently bind to dehalogenase enzymes.
  • alkynyl refers to linear, branchchained or cyclic C2-C10 (preferably C2-C6) hydrocarbon radicals containing at least one CoC bond.
  • alkylene when used, refers to a -(CH2)n- group (n is an integer generally from 0-6), which may be optionally substituted.
  • the alkylene group When substituted, the alkylene group preferably is substituted on one or more of the methylene groups with a C1-C6 alkyl group (including a cyclopropyl group or a t-butyl group), more preferably a methyl group, but may also be substituted with one or more halo groups, preferably from 1 to 3 halo groups or one or two hydroxyl groups or 0-(Cl-C6 alkyl) groups.
  • an alkylene group may be substituted with a urethane or alkoxy group (or other group) which is further substituted with a polyethylene glycol chain (of from 1 to 10, preferably 1 to 6, often 1 to 4 ethylene glycol units) to which is substituted (preferably, but not exclusively on the distal end of the polyethylene glycol chain) an alkyl chain substituted with a single halogen group, preferably a chlorine group.
  • a polyethylene glycol chain of from 1 to 10, preferably 1 to 6, often 1 to 4 ethylene glycol units
  • the alkylene group may be substituted with an amino acid side chain such as group obtained from an amino acid (a natural or unnatural amino acid) such as, for example, alanine, b-alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methionine, proline, serine, threonine, valine, tryptophan or tyrosine.
  • amino acid a natural or unnatural amino acid
  • unsubstituted shall mean substituted only with hydrogen atoms.
  • a range of carbon atoms which includes CO means that carbon is absent and is replaced with H.
  • a range of carbon atoms which is C0-C6 includes carbons atoms of 1, 2, 3, 4, 5 and 6 and for CO, H stands in place of carbon.
  • substituted or “optionally substituted” shall mean independently (i.e., where more than substituent occurs, each substituent is independent of another substituent), one or more substituents (independently, up to five substituents, preferably up to three substituents, often 1 or 2 substituents on a moiety in a compound according to the present disclosure and may include substituents, which themselves may be further substituted) at a carbon (or nitrogen) position anywhere on a molecule within context, and independently includes as substituents hydroxyl, thiol, carboxyl, cyano (CoN), nitro (N02), halogen (preferably, 1, 2 or 3 halogens, especially on an alkyl, especially a methyl group such as a trifluoromethyl), an alkyl group (preferably, C1-C10 , more preferably, C1-C6), aryl (especially phenyl and substituted phenyl for example benzyl or benzoyl), alkoxy group (preferably, C
  • substituted (each substituent being independent of another substituent) shall also mean within its context of use C1-C6 alkyl, C1-C6 alkoxy, halogen, amido, carboxamido, sulfone, including sulfonamide, keto, carboxy, C1-C6 ester (oxyester or carbonylester), C1-C6 keto, urethane -0-C(0)-NRlR2 or -N(Rl)-C(0)-0-Rl, nitro, cyano and amine (especially including a C1-C6 alkylene-NRlR2, a mono- or di- C1-C6 alkyl substituted amines which may be optionally substituted with one or two hydroxyl groups).
  • R1 and R2 are each, within context, FI or a C1-C6 alkyl group (which may be optionally substituted with one or two hydroxyl groups or up to three halogen groups, preferably fluorine).
  • substituted shall also mean, within the chemical context of the compound defined and substituent used, an optionally substituted aryl or heteroaryl group or an optionally substituted heterocyclic group as otherwise described herein.
  • Alkylene groups may also be substituted as otherwise disclosed herein, preferably with optionally substituted C1-C6 alkyl groups (methyl, ethyl or hydroxymethyl or hydroxyethyl is preferred, thus providing a chiral center), an amido group as described hereinabove, or a urethane group O-C(O)- NR1R2 group where R1 and R2 are as otherwise described herein, although numerous other groups may also be used as substituents.
  • Various optionally substituted moieties may be substituted indepencetnly with 3 or more substituents, preferably no more than 3 substituents and preferably with 1 or 2 substituents.
  • Hydroxyl refers the functional group -OH when it is a substituent in an organic compound.
  • Heterocycle refers to a heterocyclic group having from 4 to 9 carbon atoms and at least one heteroatom selected from the group consisting of N, O or S, and may be aromatic (heteroaryl) or non-aromatic.
  • heteroaryl moieties are subsumed under the definition of heterocycle, depending on the context of its use. Exemplary heteroaryl groups are described hereinabove.
  • nonaromatic heterocyclic groups for use in the present disclosure include, for example, pyrrolidinyl, pyrrolinyl, piperidinyl, piperazinyl, N-methylpiperazinyl, imidazolinyl, pyrazolidinyl, imidazolidinyl, morpholinyl, tetrahydropyranyl, azetidinyl, oxetanyl, oxathiolanyl, pyridone, 2- pyrrolidone, ethyleneurea, 1,3-dioxolane, 1,3-dioxane, 1,4-dioxane, phthalimide and succinimide, among others.
  • Heterocyclic groups can be optionally substituted with 1 to 5, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxy, carboxyalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,— SO-alkyl,—SO-substi
  • nitrogen heterocycles and heteroaryls include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, morpholino, piperidinyl, tetrahydrofuranyl, and the like as well as N-alkoxy-
  • Heteroaryl refers to a heterocyclic group having from 4 to 9 carbon atoms and at least one heteroatom selected from the group consisting of N, O or S with at least one ring of this group being aromatic. Heteroaryl groups having one or more nitrogen, oxygen, or sulfur atoms in the ring (moncyclic) such as imidazole, furyl, pyrrole, furanyl, thiene, thiazole, pyridine, pyrimidine, pyrazine, triazole, oxazole or fused ring systems such as indole, quinoline, indolizine, azaindolizine, benzofurazan, etc., among others, which may be optionally substituted as described above.
  • monocyclic such as imidazole, furyl, pyrrole, furanyl, thiene, thiazole, pyridine, pyrimidine, pyrazine, triazole, oxazole or fused ring systems such as ind
  • heteroaryl groups include nitrogen containing heteroaryl groups such as pyrrole, pyridine, pyridone, pyridazine, pyrimidine, pyrazine, pyrazole, imidazole, triazole, triazine, tetrazole, indole, isoindole, indolizine, azaindolizine, purine, indazole, quinoline, dihydroquinoline, tetrahydroquinoline, isoquinoline, dihydroisoquinoline, tetrahydroisoquinoline, quinolizine, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, imidazopyridine, imidazotriazine, pyrazinopyridazine, acridine, phenanthridine, carbazole, carbazoline, perimidine, phenanthroline,
  • Substituted heteroaryl refers to a heterocyclic group having from 4 to 9 carbon atoms and at least one heteroatom selected from the group consisting of N, O or S with at least one ring of this group being aromatic and this group being substituted with one or more substituents selected from the group consisting of halogen, alkyl, carbyloxy, carbylmercapto, alkylamino, amido, carboxyl, hydroxyl, nitro, mercapto or sulfo, whereas these generic substituent group have meanings which are identical with definitions of the corresponding groups as defined in this legend.
  • thiol refers to the group— SH.
  • thioalkoxy refers to the group— S-alkyl.
  • Alkoxyl refers to an alkyl group linked to oxygen thus: R-0-, where R is an alkyl.
  • Substituted alkyl refers to a branched or unbranched alkyl, alkenyl or alkinyl group having 1-10 carbon atoms and having substituted by one or more substituents selected from the group consisting of hydroxyl, mercapto, carbylmercapto, halogen, carbyloxy, amino, amido, carboxyl, cycloalkyl, sulfo or acyl.
  • substituent generic groups having the meanings being identical with the definitions of the corresponding groups as defined herein.
  • Halogen refers to fluorine, bromine, chlorine, and iodine atoms.
  • Acyl denotes the group -C(0)R e , where R e is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl whereas these generic groups have meanings which are identical with definitions of the corresponding groups as defined in this legend.
  • Acyloxy denotes the group --OAc, where Ac is an acyl, substituted acyl, heteroacyl or substituted heteroacyl whereas these generic groups have meanings which are identical with definitions of the corresponding groups as defined in this legend.
  • Alkylamino denotes the group --NR f R g , where R f and R g , that are independent of one another, represent hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, whereas these generic substituents have meanings which are identical with definitions of the corresponding groups defined herein.
  • Aryl refers to an aromatic carbocyclic group having from 1 to 18 carbon atoms and being a substituted (as otherwise described herein) or unsubstituted monovalent aromatic radical having a single ring (e.g., benzene, phenyl, benzyl) or condensed (fused) rings, wherein at least one ring is aromatic (e.g., naphthyl, anthracenyl, phenanthrenyl, etc.) and can be bound to the compound according to the present disclosure at any available stable position on the ring(s) or as otherwise indicated in the chemical structure presented.
  • Other examples of aryl groups, in context, may include heterocyclic aromatic ring systems.
  • Substituted aryl refers to an aromatic carbocyclic group having from 1 to 18 carbon atoms and being composed of at least one aromatic ring or of multiple condensed rings at least one of which being aromatic.
  • the ring(s) are optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, hydroxyl, carbylmercapto, alkylamino, carbyloxy, amino, amido, carboxyl, nitro, mercapto or sulfo, whereas these generic substituent group have meanings which are identical with definitions of the corresponding groups as defined in this legend.
  • Carboxyl denotes the group --C(0)OR, where R is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl , whereas these generic substituents have meanings which are identical with definitions of the corresponding groups defined herein.
  • Cycloalkyl refers to a monocyclic or polycyclic alkyl group containing 3 to 15 carbon atoms.
  • Substituted cycloalkyl refers to a monocyclic or polycyclic alkyl group containing 3 to 15 carbon atoms and being substituted by one or more substituents selected from the group consisting of halogen, alkyl, substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto or sulfo, whereas these generic substituent groups have meanings which are identical with definitions of the corresponding groups as defined in this legend.
  • Heterocycloalkyl refers to a monocyclic or polycyclic alkyl group containing 3 to 15 carbon atoms which at least one ring carbon atom of its cyclic structure being replaced with a heteroatom selected from the group consisting of N, O, S or P.
  • Substituted heterocycloalkyl refers to a monocyclic or polycyclic alkyl group containing 3 to 15 carbon atoms which at least one ring carbon atom of its cyclic structure being replaced with a heteroatom selected from the group consisting of N, O, S or P and the group is containing one or more substituents selected from the group consisting of halogen, alkyl, substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto or sulfo, whereas these generic substituent group have meanings which are identical with definitions of the corresponding groups as defined in this legend.
  • alkenyl refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2 to 40 carbon atoms, more preferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbon atoms.
  • Imidazole refers to a heterocyclic base of the general formula: C3H4N2.
  • Aralkyl group refers to, for example, a Cl -C6 alkyl group which is attached to 1 or 2 aromatic hydrocarbon rings having from 6 to 10 carbon atoms and which has a total of 7 to 14 carbon atoms, such as the benzyl, alpha-naphthylmethyl, indenylmethyl, diphenylmethyl, 2- phenethyl, 2-alpha-naphthylethyl, 3-phenylpropyl, 3-alpha-naphthylpropyl, phenylbutyl, 4-alpha- naphthylbutyl or 5-phenylpentyl groups.
  • Guanidine refers generally to the amidine of amidocarbonic acid and has the general formula of: C(NH2)3.
  • receptor is not limiting and includes any protein that interacts with the peptide (e.g., the natural or unmodified peptide), including receptors, ligands, etc.
  • aralkyl and heteroarylalkyl refer to groups that comprise both aryl or, respectively, heteroaryl as well as alkyl and/or heteroalkyl and/or carbocyclic and/or heterocycloalkyl ring systems according to the above definitions.
  • foldamers comprising peptide-oligourea compound (e.g., compounds having a polypeptide portion contiguous with or covalently coupled (i.e., "coupled") to oligomers of amino acid analogs having an N, N'- linked urea bridging unit; i.e., / ⁇ /-2-aminoethylcarbamoyl residues) demonstrate enhanced or improved properties (e.g., biological properties) relative to the parental or cognate "natural" peptide.
  • peptide-oligourea compound e.g., compounds having a polypeptide portion contiguous with or covalently coupled (i.e., "coupled"
  • oligomers of amino acid analogs having an N, N'- linked urea bridging unit i.e., / ⁇ /-2-aminoethylcarbamoyl residues
  • the oligourea portion can also contain various combinations of isosteric residues such as y-amino acid residues, substituted and unsubstituted N-(2-aminoethyl)carbamothioyl residues, substituted and unsubstituted N-(2-aminoethyl)formamidinyl residues, and substituted and unsubstituted 2-aminoethanoxycarbonyl residues.
  • the foldamers or peptide-oligourea compounds as described herein improve at least one biological property, such as a PK and/or PD characteristic, of the natural peptide.
  • the compounds of the present disclosure can adopt desired secondary structures similar to native peptides, including, e.g., linear, cyclic or helicoidal structures, they can serve as, for example, receptor ligands, effector molecules, agonists, antagonists, modulators of protein-protein interactions, orga nocatalysts or enzymes. Therefore, in certain aspects, the present description provides peptide-oligurea compounds, methods of making, and using the same.
  • a- peptide/modified or peptidomimetic compounds i.e., compounds having a natural or alpha amino acid (poly)peptide portion including at least one (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, or 10) urea amino acid substitution demonstrates enhanced or improved properties relative to the parental or cognate "natural" peptide.
  • the description provides peptide compounds or foldamers comprising a portion or sequence of alpha amino acids (i.e., an "a-peptide") that includes at least one (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, or 10) urea amino acid residue, e.g., a 1, 2-ethylene diamine residue having an N, N'-linked urea bridging unit.
  • a-peptide a portion or sequence of alpha amino acids
  • a-peptide that includes at least one (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, or 10) urea amino acid residue, e.g., a 1, 2-ethylene diamine residue having an N, N'-linked urea bridging unit.
  • a compound having a plurality e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, or 10
  • non-consecutive urea amino acid residues e.g., a 1, 2-ethylene diamine residue having an N, N'-linked urea bridging unit
  • the description provides peptide compounds or foldamers comprising a portion or sequence of alpha amino acids (i.e., an "a-peptide") that includes at least one (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, or 10) residue having a urea, thiourea, or guanidine moiety, e.g., a 1, 2-ethylene diamine residue, resulting in an N, N'- linked urea, thiourea, or guanidine bridging unit, respectively.
  • a-peptide a portion or sequence of alpha amino acids
  • a-peptide that includes at least one (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, or 10) residue having a urea, thiourea, or guanidine moiety, e.g., a 1, 2-ethylene diamine residue, resulting in an N, N'- linked urea, thiourea, or guanidine bridging unit, respectively.
  • the description also provides for a compound having a plurality (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, or 10) non-consecutive residues having a urea, thiourea, or a quinidine moiety, e.g., a 1, 2-ethylene diamine residue, resulting in an N, N'-linked urea, thiourea, or guanidine bridging unit, respectively.
  • a compound having a plurality (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, or 10) non-consecutive residues having a urea, thiourea, or a quinidine moiety e.g., a 1, 2-ethylene diamine residue, resulting in an N, N'-linked urea, thiourea, or guanidine bridging unit, respectively.
  • the present description provides a-peptide/oligourea compounds, methods of making, and using the same.
  • Amino acid ureas represent interesting classes of peptidomimetic foldamers that have previously received little attention.
  • the compounds as described herein improve at least one PK and/or PD characteristic of the natural peptide. Because the compounds as described herein can adopt desired secondary structures similar to native peptides, including, e.g., linear, cyclic or helicoidal structures, they can serve as, for example, receptor ligands, effector molecules, agonists, antagonists, modulators of protein-protein interactions, orga nocatalysts or enzymes.
  • the description provides peptide-oligourea compounds that comprise at least one substitution of an a-amino acid of the parent peptide sequence with a urea amino acid residue.
  • the oligourea residue is substituted with an identical or homologous (i.e., conservative change) proteinogenic amino acid side chain.
  • the description provides peptide-oligourea compounds in which a plurality of non-consecutive a-amino acids of the parent peptide sequence are substituted with a urea amino acid residue, a thiourea amino acid residue, or a guanidine amino acid residue.
  • the substitutions can be located anywhere within the parental polypeptide chain.
  • the urea amino acid residues are coupled, joined to or contiguous with the a-peptide amino acid backbone.
  • the urea amino acid residue or residues are "fused" to a terminus, e.g., amino terminus, carboxy terminus or both, of an a-amino acid peptide.
  • the urea amino acid residue or residues are substituted with an identical or homologous (i.e., conservative change) proteinogenic amino acid side chain.
  • the description provides a peptide-oligourea compound or foldamer comprising a plurality of amino acids substitution to the parent peptide with a residue selected from a urea (e.g., substituted or unsubstituted N-2-aminoethylcarbamoyl residue), a thiourea (e.g., substitute or unsubstituted N-(2-aminoethyl)carbamothioyl), and a guanidine (e.g., substitute or unsubstituted N-(2-aminoethyl)formamidinyl), wherein at least one non-consecutive amino acid has been monosubstituted by an aminourea, a thiourea, or a guanidine.
  • a urea e.g., substituted or unsubstituted N-2-aminoethylcarbamoyl residue
  • a thiourea e.g
  • the substituted residue e.g., the monosubstituted amino acid
  • the substituted residue is located in the first 4 a mino acids (N-terminal) of the peptide (e.g., the first amino acid (N-terminal), second amino acid, third amino acid, or fourth amino acid of the peptide).
  • the substituted residue e.g., the monosubstituted amino acid
  • the peptide e.g., the last amino acid (C-terminal), the second to last amino acid, the third to last amino acid, or fourth to last amino acid of the peptide.
  • the substituted residue e.g., the monosubstituted amino acid
  • the substituted residue is located at or within 3 amino acids of a peptidase degradation site of the peptide (e.g., within 2 amino acids or within 1 amino acid of a peptidase degradation site of the peptide).
  • the substituted residue e.g., the monosubstituted amino acid
  • the substituted residue is located at or within 3 amino acids of an amino acid that is key for the interaction between the protein and a receptor, ligand or other polypeptide or peptide that interacts with the natural/native peptide (e.g., within 2 amino acids or within 1 amino acid of an amino acid that is key for the interaction between the protein and a receptor, ligand or other polypeptide or peptide that interacts with the peptide).
  • the substituted residue e.g., the monosubstituted amino acid
  • the substituted residue is located at or within 3 amino acids of an amino acid that is key for at least one pharmacokinetic property of the peptide (e.g., within 2 amino acids or within 1 amino acid of an amino acid that is key for at least one pharmacokinetic property of the peptide).
  • the substituted residue e.g., the monosubstituted amino acid
  • the substituted residue is located at or within 3 amino acids of an amino acid that is key for at least one physical property of the peptide (e.g., within 2 amino acids or within 1 amino acid of an amino acid that is key for at least one physical property of the peptide).
  • the substituted residue e.g., the monosubstituted amino acid
  • the peptide is 4 or more amino acids (e.g., at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acids).
  • the number of amino acids of the parent peptide is equal to or less than 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35,
  • the urea portion of the compound comprises at least one (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15) peptidomimetic urea residue as described herein, for example, a 1, 2-ethylene diamine residue having an N, N'- linked urea bridging unit.
  • the peptidomimetic oligourea portion further comprises at least one other modified or peptidomimetic amino acid residue, such as, an amino acid analog, e.g., one or more y-amino acid residue, as well as other members of the y-peptide superfamily including y-peptides and oligocarbamates or a combination thereof.
  • At least one other modified or peptidomimetic amino acid residue is a N-( 2- aminoethyl)carbamoyl residue, a substituted or unsubstituted N-(2-aminoethyl)carbamothioyl residue, a substituted or unsubstituted N-(2-aminoethyl)formamidinyl residue, a substituted or unsubstituted 2-aminoethanoxycarbonyl residue or a combination or oligomer thereof.
  • the peptide-oligourea, foldamer, or compound of the present disclosure is capable of binding specifically to a target, e.g., a protein such as a receptor or other polypeptide or peptide, or small molecule, similar to the natural peptide.
  • a target e.g., a protein such as a receptor or other polypeptide or peptide, or small molecule, similar to the natural peptide.
  • the peptide comprises at least two (e.g., at least 3, 4, 5, 6, 7, 8, 9, or 10) non-consecutive urea amino acids or urea peptidomimetic amino acid residues, or modified versions thereof, having an N, N'-linked urea bridging unit.
  • At least one of the modified or pseudoamino acid residues is a N-( 2- aminoethyl)carbamoyl residue, a substituted or unsubstituted N-(2-aminoethyl)carbamothioyl residues, a substituted or unsubstituted N-(2-aminoethyl)formamidinyl residues, a substituted or unsubstituted 2-aminoethanoxycarbonyl residue or a combination thereof.
  • the description provides urea amino acid-containing peptides that adopt stable secondary structures, including, e.g., linear, cyclic, or helicoidal, tertiary structure, and/or quaternary structures.
  • the urea amino acid (i.e., peptidomimetic residue) includes a substituted or unsubstituted / ⁇ /-2-aminoethylcarbamoyl residue a y-amino acid residue, a substituted and unsubstituted N-(2-aminoethyl)carbamothioyl residues, a substituted and unsubstituted N-(2-aminoethyl)formamidinyl residues, and a substituted and unsubstituted 2- aminoethanoxycarbonyl residues.
  • the peptide comprises two or more non-consecutive peptidomimetic residues.
  • the urea amino acid is substituted with a proteinogenic amino acid side chain.
  • compounds according to the present disclosure are capable of binding specifically to a target, e.g., a protein such as a receptor, ligand or other polypeptide or peptide, or small molecule, similar to the native or natural peptide.
  • a target e.g., a protein such as a receptor, ligand or other polypeptide or peptide, or small molecule, similar to the native or natural peptide.
  • the peptide- oligourea ligand compound comprises a peptide comprising a plurality of N, N'-linked urea L/-2- aminoethyl residues as y-amino acid residue analogues.
  • the peptide portion comprises a-amino acids.
  • the peptide-oligourea ligand compound comprises an amino acid sequence contiguous with or coupled to an oligourea portion including one or more oligourea peptidomimetic residues, wherein the peptidomimetic residue is selected from the group consisting of substituted and unsubstituted / ⁇ /-2-aminoethylcarbamoyl residue as well as isosteric residus such as y-amino acid residues, substituted and unsubstituted N- (2-aminoethyl)carbamothioyl residues, substituted and unsubstituted N-(2- aminoethyl)formamidinyl residues, and substituted and unsubstituted 2-aminoethanoxycarbonyl residues, and a combination thereof.
  • the peptide-oligourea ligand compound comprises two or more (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, or 10) urea peptidomimetic residues, wherein at least one (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) urea peptidomimetic residue is a non-consecutive substitution.
  • the urea amino acid or urea peptidomimetic residue comprises an acyclic y-amino acid residue.
  • the urea amino acid or urea peptidomimetic residue comprises an N-( 2- aminoethyl)carbamoyl residue, acyclic y-amino acid residue or a combination thereof.
  • the urea amino acid or urea peptidomimetic residue comprises an isosteric residue such as y-amino acid residue, substituted or unsubstituted N-(2- aminoethyl)carbamothioyl residue, substituted or unsubstituted N-(2-aminoethyl)formamidinyl residue, substituted or unsubstituted 2-aminoethanoxycarbonyl residue or a combination thereof.
  • the description provides compounds comprising a peptide comprises one non-consecutive urea amino acid or urea peptidomimetic residue as described herein, e.g. a N, N'-linked urea 1,2-ethylene diamine residue.
  • the urea amino acid includes a peptidomimetic 1,2-ethylene diamine residue with N, N'-linked urea bridging unit.
  • the peptidomimetic is residue a substitute or unsubstituted N- 2- aminoethylcarbamoyl residue.
  • the compounds comprise a polypeptide portion including at least one a-, y-, d- amino acid, derivative or combination thereof, which is contiguous with or coupled to a plurality of peptidomimetic 1,2-ethylene diamine residues having an N, N'-linked urea bridging unit, wherein at least one residue is non-consecutive with other peptidomimetic residues.
  • the peptide compound comprises a substituted or unsubstituted N-(2-aminoethyl)carbamoyl residue.
  • the compound comprises an urea amino acid or peptidomimetic residue contiguous with or covalently linked or joined to at least one of the amino terminus (N'), the carboxyl terminus (C'), within the peptide sequence or a combination thereof.
  • the compound comprises 1, 2, 3, 4, 5, 6, 7, 8,
  • carbamoyl or urea-substitued amino residues e.g., amino acid derivatives with N, N'-linked urea bridging unit
  • carbamoyl or urea-substitued amino residues e.g., amino acid derivatives with N, N'-linked urea bridging unit
  • the residue is at least one of or a plurality of a y-amino acid residue, substituted or unsubstituted N-(2- aminoethyl)carbamothioyl residue, substituted or unsubstituted N-(2-aminoethyl)formamidinyl residue, substituted or unsubstituted 2-aminoethanoxycarbonyl residue or combination thereof.
  • the urea amino acid is an substituted or unsubstited N-(2- aminoethyl)carbamoyl residue.
  • the aminoethylcarbamoyl residue is substituted with a proteinogenic amino acid side chain.
  • the compounds can further comprise at least one additional chemical modification.
  • the chemical modification includes at least one of, for example, acetylation, phosphorylation, methylation, glycosylation, prenylation, isoprenylation, farnesylation, geranylation, pegylation, a disulfide bond, or combination thereof.
  • the description provides pharmaceutically acceptable acid and base salt forms of the peptide-oligourea compounds (i.e., the peptide-oligourea compounds or foldamers) described herein.
  • the foldamers as described herein including pharmaceutically acceptable salts thereof are useful for the preparation of a medicament and/or the treatment, prevention or amelioration of at least one symptom of a disease or disorder in a subject.
  • the compounds of the present disclosure may optionally be administered with at least one of a pharmaceutically acceptable excipient, pharmacologically active agent or a combination thereof.
  • a pharmaceutically acceptable carrier or excipient comprising an effective amount of a compound as described herein, and a pharmaceutically acceptable carrier or excipient.
  • the compounds comprising at least one N, N'-linked urea residue (e.g., / ⁇ /-2-aminoethylcarbamoyl) of formula II:
  • Ra, R'a, R"a and R"'a are independently selected from the group consisting of a hydrogen atom, an amino acid side chain, a (C1-C10) alkyl, (C1-C10) alkenyl, (C1-C10) alkynyl, (C5- C12) monocyclic or bicyclic aryl, (C5-C14) monocyclic or bicyclic aralkyl, (C5-C14) monocyclic or bicyclic heteroalkyl and (C1-C10) monocyclic or bicyclic heteroaryl group comprising up to 5 heteroatoms selected from N, O, and S, said groups being able to be non-substituted or substituted by 1 to 6 substituents further selected from the group consisting of: a halogen atom, an NO2, OH, amidine, benzamidine, imidazole, alkoxy, (C1-C4) alkyl, NH2, CN, trihalomethyl, (C1
  • R a , R' a , R" a and R'" a are independently selected from a chemical moiety described herein.
  • the / ⁇ /-2-aminoethylcarbamoyl residue is independently selected from the group consisting of :
  • R is independently selected from the group consisting of hydrogen, any side chain of a natural amino acid, linear, branched or cyclic Cl-C6-alkyl, alkenyl or alkynyl; mono- or - bicyclic aryl, mono or bicyclic heteroaryl having up to five heteroatoms selected from N, O and S; mono or bicyclic a ryl-Cl-C6-a Ikyl, alkenyl or alkynyl; Cl-C6-alkyloxy, aryloxy, heteroaryloxy, thio, Cl- C6-alkylthio, amino, mono ordi-Cl-C6-alkylamino, carboxylic acid, carboxamide mono- or di-Cl-C6- alkylcarboxamine, sulfonamide, urea, mono-di or tri-substituted urea, thiourea, guanidine.
  • R 1 is independently selected from the group consisting of hydrogen, linear, branched or cyclic Cl-C6-alkyl, alkenyl or alkynyl; mono- or -bicyclic aryl, mono or bicyclic heteroaryl having up to five heteroatoms selected from N, O and S
  • R 2 is independently selected from the group consisting of hydrogen, linear, branched or cyclic Cl-C6-alkyl, alkenyl or alkynyl; mono- or -bicyclic aryl, mono or bicyclic heteroaryl having up to five heteroatoms selected from N, O and S
  • R1 and R2 are each, within context, H or a C1-C6 alkyl group.
  • V and W are combined , together with the carbon atoms to which they are bonded, and independently define a substituted or unsubstituted, monocyclic or bicyclic C3-C10 cycloalkyl, cycloalkenyl or heterocyclic ring having one or more N, O, or S atom(s) as the heteroatom(s).
  • the peptide portion may comprise an a-amino acid sequence corresponding to a biologically active peptide or a fragment thereof.
  • the compound as described herein is biologically active, for example the compound has the same, similar, or better biological activity as the natural/parent peptide.
  • the compounds as described herein are enzymatically active.
  • the compounds as described herein are configured to bind target proteins.
  • the target protein is a cytosolic protein.
  • the target protein is a membrane protein.
  • the membrane protein is a receptor.
  • the receptor is a growth factor receptor or a G-Protein Coupled Receptor (GPCR) or a fragment thereof.
  • GPCR G-Protein Coupled Receptor
  • the description provides compounds comprising a peptide sequence with a plurality of coupled urea amino acids comprising a N, N'-linked urea residues, wherein at least one of the urea amino acids is non-consecutive with other urea amino acids.
  • compounds as described herein adopt well-defined helical secondary structures akin to that of a-polypeptides, and can enhance or improve the beneficial properties of the cognate or parental "natural" peptide.
  • y-amino acids are characterized by a greater chemical diversity (seven substitution positions versus three for a-amino acids) and conformational versatility.
  • the y-peptide backbone can be seen as the prototypic member of a la rger fa mily (i.e. y- peptide superfamily or lineage) of peptidomimetic backbones and com binations thereof, all sharing an isosteric relationship (e.g.oligocarbamates, N,N'- linked oligo(thio)ureas, oligoguanidines, oligomers of 6-aminoxy acids, sulfonamidopeptides).
  • the constituent units in these backbones are endowed with different properties, their combination represent an opportunity to generate new heterogeneous backbone oligomers with defined secondary structures, thus further expanding the chemical space of foldamers in the y-peptide superfamily.
  • the compounds as described herein including pharmaceutically acceptable salts thereof are useful for the preparation of a medicament and/or the treatment of disease in a subject.
  • a salt of a compound is desired and the compound is produced in the form of the desired salt, it can be subjected to purification as such.
  • the compound is dissolved or suspended in a suitable organic solvent, followed by addition of an acid or a base to form a salt.
  • the description provides compositions comprising an effective amount of a peptide-oligourea compounds as described herein, and a pharmaceutically acceptable carrier or excipient.
  • the compounds of the present disclosure may optionally be administered with at least one of a pharmaceutically acceptable excipient, pharmacologically active agent or a combination thereof.
  • a pharmaceutically acceptable excipient pharmacologically active agent or a combination thereof.
  • These novel, unnatural peptidomimetics are resistant or wholly immune to peptidase and protease degradation and are conformationally restrained. Thus, they are useful as tools to model peptide and protein conformations in aqueous solutions.
  • the compounds are also useful as non- enzymatically degradable probes to mimic protein behavior in solution.
  • the description further provides the compositions comprising an effective amount of a peptide-oligourea compound as described herein, and a pharmaceutically acceptable carrier or excipient.
  • Certain compounds of the present disclosure and their salts may exist in more than one crystal form and the invention of the present disclosure includes each crystal form and mixtures thereof. Certain compounds of the present disclosure and their salts may also exist in the form of solvates, for example hydrates, and the invention of the present disclosure includes each solvate and mixtures thereof.
  • Certain compounds of the present disclosure may contain one or more chiral centers, and exist in different optically active forms.
  • compounds of the invention may contain one chiral center, the compounds exist in two enantiomeric forms and the present invention includes both enantiomers and mixtures of enantiomers, such as racemic mixtures.
  • the enantiomers may be resolved by methods known to those skilled in the art, for example by formation of diastereoisomeric salts which may be separated, for example, by crystallization; formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer- specific reagent, for example enzymatic esterification; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent.
  • a further step may be used to liberate the desired enantiomeric form.
  • specific enantiomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.
  • a compound of the present disclosure may exist in diastereoisomeric forms.
  • the diastereoisomeric compounds may be separated by methods known to those skilled in the art, for example chromatography or crystallization and the individual enantiomers may be separated as described above.
  • the invention of the present disclosure includes each diastereoisomer of compounds of the present disclosure and mixtures thereof.
  • Certain compounds of the present disclosure may exist in different tautomeric forms or as different geometric isomers, and the invention of the present disclosure includes each tautomer and/or geometric isomer of compounds of the present disclosure and mixtures thereof.
  • Certain compounds of the present disclosure may exist in different stable conformational forms which may be separable. Torsional asymmetry due to restricted rotation about an asymmetric single bond, for example because of steric hindrance or ring strain, may permit separation of different conformers.
  • the invention of the present disclosure includes each conformational isomer of compounds of the present disclosure and mixtures thereof.
  • Certain compounds of the present disclosure may exist in zwitterionic form and the invention of the present disclosure includes each zwitterionic form of compounds of the present disclosure and mixtures thereof.
  • the present disclosure encompasses all possible isomers including tautomers and mixtures thereof. Where chiral carbons lend themselves to two different enantiomers, both enantiomers are contemplated as well as procedures for separating the two enantiomers.
  • the present disclosure also relates to pharmaceutically acceptable salts, racemates, and optical isomers thereof.
  • the compounds of the present disclosure typically contain one or more chiral centers. Accordingly, the present disclosure is intended to include racemic mixtures, diasteromers, enantiomers and mixture enriched in one or more steroisomer.
  • the scope of the invention of the present disclosure as described and claimed encompasses the racemic forms of the compounds as well as the individual enantiomers and non-racemic mixtures thereof.
  • Many of the compounds of the present disclosure may be provided as salts with pharmaceutically compatible counterions (i.e., pharmaceutically acceptable salts).
  • pharmaceutically acceptable salt is used throughout the specification to describe, where applicable, a salt form of one or more of the compounds or prodrugs described herein which are presented to increase the solubility of the compound in the gastic juices of the patient's gastrointestinal tract in order to promote dissolution and the bioavailability of the compounds.
  • Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids, where applicable. Suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium, magnesium and ammonium salts, among numerous other acids and bases well known in the pharmaceutical art. Sodium and potassium salts are particularly preferred as neutralization salts of the phosphates according to the present disclosure.
  • the description provides pharmaceutically acceptable salts of the modified peptides as described herein, which retain the biological effectiveness and properties of the parent compounds and which are not biologically or otherwise harmful as the dosage administered.
  • the compounds of present disclosure are capable of forming both acid and base salts by virtue of the presence of amino and carboxy groups respectively.
  • a "pharmaceutically acceptable counterion” is an ionic portion of a salt that is not toxic when released from the salt upon administration to a recipient.
  • Pharmaceutically compatible salts may be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free base forms.
  • Acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrogen bisulfide, hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid, as well as organic acids such as para-toluenesulfonic, salicylic, tartaric, bitartaric, ascorbic, maleic, besylic, fumaric, gluconic, glucuronic, formic, glutamic, methanesulfonic, ethanesulfonic, benzenesulfonic, lactic, oxalic, parabromophenylsulfonic, carbonic, succinic, citric, benzoic and acetic acid, and related inorganic and organic acids.
  • inorganic acids such as hydrogen bisulfide, hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid
  • organic acids such as para-toluenesulfonic, salicylic, tartaric, bitartaric, ascor
  • Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate , sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-1,6- dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate
  • Preferred pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and especially those formed with organic acids such as maleic acid.
  • Suitable bases for forming pharmaceutically acceptable salts with acidic functional groups include, but are not limited to, hydroxides of alkali metals such as sodium, potassium, and lithium; hydroxides of alkaline earth metal such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, and organic amines, such as unsubstituted or hydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine; tributyl amine; pyridine; N-methyl,N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2- hydroxy-lower alkyl amines), such as mono-, bis-, or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert- but
  • prodrug forms of the above described compounds, wherein the prodrug is metabolized in vivo to produce an analog or derivative as set forth above. Indeed, some of the described compounds may be a prodrug for another analog or derivative.
  • prodrug is well understood in the art and refers to an agent which is converted into the parent drug in vivo by some physiological chemical process (e.g., a prodrug on being brought to the physiological pH is converted to the desired drug form). For example, see Remington 's Pharmaceutical Sciences, 1980, vol. 16, Mack Publishing Company, Easton, Pa., 61 and 424.
  • Pro-drugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not.
  • the prodrug may also have improved solubility in pharmacological compositions over the parent drug.
  • An example, without limitation, of a pro-drug would be a compound of the present disclosure wherein it is administered as an ester (the "pro-drug") to facilitate transmittal across a cell membrane where water solubility is not beneficial, but then it is metabolically hydrolyzed to the carboxylic acid once inside the cell where water solubility is beneficial.
  • Pro-drugs have many useful properties.
  • a pro-drug may be more water soluble than the ultimate drug, thereby facilitating intravenous administration of the drug.
  • a pro-drug may also have a higher level of oral bioavailability than the ultimate drug. After administration, the prodrug is enzymatically or chemically cleaved to deliver the ultimate drug in the blood or tissue.
  • Exemplary pro-drugs upon cleavage release the corresponding free acid, and such hydrolyzable ester-forming residues of the compounds of the present disclosure include but are not limited to carboxylic acid substituents (e.g., -C(0)2H or a moiety that contains a carboxylic acid) wherein the free hydrogen is replaced by (Cl -C4)alkyl, (Cz-C12)alkanoyloxymethyl, (C4-C9)l- (alkanoyloxy)ethyl, l-methyl-l-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, l-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, l-methyl-l-10 (alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N- (alkoxycarbonyl)aminomethyl having
  • Other exemplary pro-drugs release an alcohol or amine of a compound of the present disclosure wherein the free hydrogen of a hydroxyl or amine substituent is replaced by (Cl - C6)alkanoyloxymethyl, l-((Cl-C6)alkanoyloxy)ethyl, l-methyl-l-((CI-C6)alkanoyloxy)ethyl, (Cl - C6)alkoxycarbonyl-oxymethyl, N-(CI -C6)alkoxycarbonylamino- 20 methyl, succinoyl, (Cl - C6)alkanoyl, a-amino(C l-C4)alkanoyl, arylactyl and a-aminoacyl, or a-aminoacyl-a-aminoacyl wherein said a-aminoacyl moieties are independently any of the naturally occurring L-amino acids found in proteins, -P(0)(OH)2'
  • protecting group means temporary substituents which protect a potentially reactive functional group from undesired chemical transformations.
  • protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively.
  • the field of protecting group chemistry has been reviewed (Greene, T.W.; Wuts, P.G.M. Protective 30 Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991). Protected forms of the inventive compounds are included within the scope of the present disclosure.
  • chemically protected form pertains to a compound in which one or more reactive functional groups are protected from undesirable chemical reactions, that is, are in the form of a protected or protecting group (also known as a masked or masking group). It may be convenient or desirable to prepare, purify, and/or handle the active compound in a chemically protected form.
  • the aldehyde or ketone group is readily regenerated by hydrolysis using a large excess of water in the presence of acid.
  • a carboxylic acid group may be protected as an ester or an amide, for example, as: a benzyl ester; a t-butyl ester; a methyl ester; or a methyl amide.
  • the compounds disclosed herein can be used in the treatment of disorders associated with pathogen infection.
  • Disorders associated with infection by pathogens include, but are not limited to, infection by viruses (DNA viruses, RNA viruses, animal viruses, and the like), bacteria (e.g., gram positive bacteria, gram negative bacteria, acid-fast bacteria, and the like), fungi, parasitic microbes, nematodes, and the like.
  • viruses DNA viruses, RNA viruses, animal viruses, and the like
  • bacteria e.g., gram positive bacteria, gram negative bacteria, acid-fast bacteria, and the like
  • fungi e.g., parasitic microbes, nematodes, and the like.
  • pharmaceutically acceptable derivative is used throughout the specification to describe any pharmaceutically acceptable prodrug form (such as an ester, amide other prodrug group) which, upon administration to a patient, provides directly or indirectly the present compound or an active metabolite of the present compound.
  • pharmaceutically acceptable derivative such as an ester, amide other prodrug group
  • independently is used herein to indicate that the variable, which is independently applied, varies independently from application to application.
  • treatment includes any treatment of a condition or disease in an animal, particularly a mammal, more particularly a human, and includes: (i) preventing the disease or condition from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (ii) inhibiting the disease or condition, i.e. arresting its development; relieving the disease or condition, i.e. causing regression of the condition; or (iii) ameliorating or relieving the conditions caused by the disease, i.e. symptoms of the disease.
  • the term "effective” is used to describe an amount of a compound, composition or component which, when used within the context of its intended use, effects an intended result.
  • therapeutically effective amount refers to that amount which is sufficient to effect treatment, as defined herein, when administered to a mammal in need of such treatment.
  • the therapeutically effective amount will vary depending on the subject and disease state being treated, the severity of the affliction and the manner of administration, and may be determined routinely by one of ordinary skill in the art.
  • Suitable routes for administration include oral, peroral, rectal, vassal, topical (including ocular, buccal and sublingual), vaginal and parental (including subcutaneous, intramuscular, intravitreous, intravenous, intradermal, intrathecal and epidural).
  • the preferred route of administration will depend upon the condition of the patient, the toxicity of the compound and the site of infection, among other considerations known to the clinician.
  • the therapeutic composition of the present disclosure comprises about 1% to about 95% of the active ingredient, single-dose forms of administration preferably comprising about 20% to about 90% of the active ingredient and administration forms which are not single-dose preferably comprising about 5% to about 20% of the active ingredient.
  • Unit dose forms are, for example, coated tablets, tablets, ampoules, vials, suppositories or capsules.
  • Other forms of administration are, for example, ointments, creams, pastes, foams, tinctures, lipsticks, drops, sprays, dispersions and the like. Examples are capsules containing from about 0.05 g to about 1.0 g of the active ingredient.
  • compositions of the present disclosure are prepared in a manner known per se, for example by means of conventional mixing, granulating, coating, dissolving or lyophilizing processes.
  • solutions of the active ingredient, and in addition also suspensions or dispersions, especially isotonic aqueous solutions, dispersions or suspensions are used, it being possible for these to be prepared before use, for example in the case of lyophilized compositions which comprise the active substance by itself or together with a carrier, for example mannitol.
  • the pharmaceutical compositions can be sterilized and/or comprise excipients, for example preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizing agents, salts for regulating the osmotic pressure and/or buffers, and they are prepared in a manner known per se, for example by means of convential dissolving or lyophilizing processes.
  • the solutions or suspensions mentioned can comprise viscosity-increasing substances, such as sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone or gelatin.
  • Pharmaceutically acceptable forms include, for example, a gel, lotion, spray, powder, pill, tablet, controlled release tablet, sustained release tablet, rate controlling release tablet, enteric coating, emulsion, liquid, salts, pastes, jellies, aerosols, ointments, capsules, gel caps, or any other suitable form that will be obvious to one of ordinary skill in the art.
  • Suspensions in oil comprise, as the oily component, the vegetable, synthetic or semi synthetic oils customary for injection purposes.
  • Oils which may be mentioned are, in particular, liquid fatty acid esters which contain, as the acid component, a long-chain fatty acid having 8-22, in particular 12-22, carbon atoms, for example lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, arachidinic acid, behenic acid or corresponding unsaturated acids, for example oleic acid, elaidic acid, euric acid, brasidic acid or linoleic acid, if appropriate with the addition of antioxidants, for example vitamin E, .beta.
  • the alcohol component of these fatty acid esters has not more than 6 carbon atoms and is mono- or polyhydric, for example mono-, di- or trihydric alcohol, for example methanol, ethanol, propanol, butanol, or pentanol, or isomers thereof, but in particular glycol and glycerol.
  • Fatty acid esters are therefore, for example: ethyl oleate, isopropyl myristate, isopropyl palmitate, "Labrafil M 2375” (polyoxyethylene glycerol trioleate from Gattefosee, Paris), "Labrafil M 1944 CS” (unsaturated polyglycolated glycerides prepared by an alcoholysis of apricot kernel oil and made up of glycerides and polyethylene glycol esters; from Gattefosee, Paris), “Labrasol” (saturated polyglycolated glycerides prepared by an alcoholysis of TCM and made up of glycerides and polyethylene glycol esters; from Gattefosee, Paris) and/or "Miglyol 812" (triglyceride of saturated fatty acids of chain length C8 to C12 from Huls AG, Germany), and in particular vegetable oils, such as cottonseed oil, almond oil, olive oil, castor oil, sesame
  • the preparation of the injection compositions is carried out in the customary manner under sterile conditions, as are bottling, for example in ampoules or vials, and closing of the containers.
  • compositions for oral use can be obtained by combining the active ingredient with one or more solid carriers, if appropriate granulating the resulting mixture, and, if desired, processing the mixture or granules to tablets or coated tablet cores, if appropriate by addition of additional excipients.
  • Suitable carriers are, in particular, fillers, such as sugars, for example lactose, sucrose, mannitol or sorbitol cellulose preparations and/or calcium phosphates, for example tricalcium phosphate, or calcium hydrogen phosphate, and furthermore binders, such as starches, for example maize, wheat, rice or potato starch, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and/or polyvinyl-pyrrolidine, and/or, if desired, desintegrators, such as the above mentioned starches, and furthermore carboxy methyl-starch, cross-linked polyvinylpyrrolidone, alginic acid or a salt thereof, such as sodium alginate.
  • fillers such as sugars, for example lactose, sucrose, mannitol or sorbitol cellulose preparations and/or calcium phosphates, for example tricalcium phosphate, or calcium hydrogen phosphate
  • binders such as starches, for example maize
  • Additional excipients are, in particular, flow regulators and lubricants, for example salicylic acid, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol, or derivatives thereof.
  • flow regulators and lubricants for example salicylic acid, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol, or derivatives thereof.
  • Coated tablet cores can be provided with suitable coatings which, if appropriate, are resistant to gastric juice, the coatings used being, inter alia, concentrated sugar solutions, which, if appropriate, comprise gum arabic, talc, polyvinylpyrrolidine, polyethylene glycol and/or titanium dioxide, coating solutions in suitable organic solvents or solvent mixtures or, for the preparation of coatings which are resistant to gastric juice, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate.
  • controlled release it is meant for purposes of the present disclosure that therapeutically active compound is released from the preparation at a controlled rate or at a specific site, for example, the intestine, or both such that therapeutically beneficial blood levels (but below toxic levels) are maintained over an extended period of time, e.g., providing a 12 hour or a 24 hour dosage form.
  • rate controlling polymer includes hydrophilic polymers, hydrophobic polymers or mixtures of hydrophilic and/or hydrophobic polymers that are capable of retarding the release of the compounds in vivo.
  • many of the same polymers can be utilized to create an enteric coating of a drug, drug suspension, or drug matrix. It is within the skill of those in the art to modify the coating thickness, permeability, and dissolution characteristics to provide the desired controlled release profile (e.g., drug release rate and locus) without undue experimentation.
  • Suitable controlled release polymers to be used in this invention include hydroxyalkylcellulose, such as hydroxypropylcellulose and hydroxypropylmethyl-cellulose; poly(ethylene)oxide; alkylcellulose such as ethycellulose and methylcellulose; carboxymethylcellulose; hydrophilic cellulose derivatives; polyethylene glycol; polyvinylpyrrolidone; cellulose acetate; cellulose acetate butyrate; cellulose acetate phthalate; cellulose acetate trimellitate; polyvinylacetate phthalate; hydroxypropylmethylcellulose phthalate; hydroxypropylmethylcellulose acetate succinate; poly(alkyl methacrylate); and poly (vinyl acetate).
  • Other suitable hydrophobic polymers include polymers or copolymers derived from acrylic or methacrylic acid esters, copolymers of acrylic and methacrylic acid esters, zein, waxes, shellac and hydrogenated vegetable oils.
  • the controlled release preparation of the present disclosure contains about 5 and 75% by weight, preferably about 20 and 50% by weight, more preferably about 30 to 45% by weight controlled release polymer(s) and about 1 to 40% by weight, preferably about 3 to 25% by weight active compounds.
  • the controlled release preparation according to the present disclosure can preferably include auxiliary agents, such as diluents, lubricants and/or melting binders.
  • the excipients are selected to minimize the water content of the preparation.
  • the preparation includes an antioxidant.
  • Suitable diluents include pharmaceutically acceptable inert fillers such as microcrystalline cellulose, lactose, dibasic calcium phosphate, saccharides, and/or mixtures of any of the foregoing.
  • the diluent is suitably a water soluble diluent.
  • diluents include microcrystalline cellulose such as Avicel phll2, Avicel pHlOl and Avicel pH102; lactose such as lactose monohydrate, lactose anhydrous, and Pharmatose DCL 21; dibasic calcium phosphate such as Emcompress; mannitol; starch; sorbitol; sucrose; and glucose.
  • Suitable lubricants including agents that act on the flowability of the powder to be compressed are, for example, colloidal silicon dioxide such as Aerosil 200; talc; stearic acid, magnesium stearate, and calcium stearate.
  • Suitable low temperature melting binders include polyethylene glycols such as PEG 6000; cetostearyl alcohol; cetyl alcohol; polyoxyethylene alkyl ethers; polyoxyethylene castor oil derivatives; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene stearates; poloxamers; and waxes.
  • an antioxidant compound can be included.
  • Suitable antioxidants include sodium metabisulfite; tocopherols such as alpha, beta, or delta-tocopherol tocopherol esters and alpha-tocopherol acetate; ascorbic acid or a pharmaceutically acceptable salt thereof; ascorbyl palmitate; alkyl gallates such as propyl gallate, Tenox PG, Tenox s-1; sulphites or a pharmaceutically acceptable salt thereof; BHA; BHT; and monothioglycerol.
  • the controlled release preparation according to the present disclosure preferably can be manufactured by blending the compounds with the controlled release polymer(s) and auxiliary excipients followed by direct compression.
  • Other methods for manufacturing the preparation include melt granulation.
  • Preferred melt granulation techniques include melt granulation together with the rate controlling polymer(s) and diluent(s) followed by compression of the granules and melt granulation with subsequent blending with the rate controlling polymer(s) and diluents followed by compression of the blend.
  • the blend and/or granulate can be screened and/or mixed with auxiliary agents until an easily flowable homogeneous mixture is obtained.
  • Oral dosage forms of the controlled release preparation according to the present disclosure can be in the form of tablets, coated tablets, enterically coated tablets or can be multiparticulate, such as in the form of pellets or mini-tablets.
  • capsules such as hard or soft gelatin capsules, can contain the multiparticulates.
  • the multiparticulate oral dosage forms can comprise a blend of at least two populations of pellets or mini-tablets having different controlled-release in vitro and/or in vivo release profiles.
  • one of the pellet or mini-tablet populations can comprise immediate release multiparticulate, such as multiparticulates formed by conventional means.
  • the controlled release matrix tablets or multiparticulates of the present disclosure can be coated with a controlled release polymer layer so as to provide additional controlled release properties.
  • Suitable polymers that can be used to form this controlled release layer include the rate controlling polymers listed above.
  • the tablets, pellets or mini-tablets according to the present disclosure can be provided with a light-protective and/or cosmetic film coating, for example, film-formers, pigments, anti-adhesive agents and plasticizers.
  • a film former may consist of fast-dissolving constituents, such as low-viscosity hydroxypropylmethylcelluose, for example Methocel E5 or D14 or Pharmacoat 606 (Shin-Etsu).
  • the film coating may also contain excipients customary in film-coating procedures, such as light-protective pigments, for example iron oxide, or titanium dioxide, anti-adhesive agents, for example talc, and also suitable plasticizers such as PEG 400, PEG 6000, and diethyl phthalate or triethyl citrate.
  • light-protective pigments for example iron oxide, or titanium dioxide
  • anti-adhesive agents for example talc
  • suitable plasticizers such as PEG 400, PEG 6000, and diethyl phthalate or triethyl citrate.
  • the controlled release polymer of the present disclosure may consist of a hydrogel matrix.
  • the compounds can be compressed into a dosage form containing a rate controlling polymer, such as HPMC, or mixture of polymers which when wet will swell to form a hydrogel.
  • a rate controlling polymer such as HPMC
  • HPMC high density polyethylene glycol
  • the rate of release from this dosage form is controlled both by diffusion from the swollen tablet mass and by erosion of the tablet surface over time.
  • the rate of release may be controlled both by the amount of polymer per tablet and by the inherent viscosities of the polymers used.
  • Dyes or pigments can be admixed to the tablets or coated tablet coatings, for example for identification or characterization of different doses of active ingredient.
  • compositions which can be used orally, are also hard capsules of gelatin and soft, closed capsules of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the hard capsules can contain the active ingredient in the form of granules, mixed for example with fillers, such as maize starch, binders and/or lubricants, such as talc or magnesium stearate, and stabilizers if appropriate.
  • the active ingredient is preferably dissolved or suspended in suitable liquid excipients, such as greasy oils, paraffin oil or liquid polyethylene glycols or fatty acid esters of ethylene glycol or propylene glycol, it being likewise possible to add stabilizers and detergents, for example of the polyethylene sorbitan fatty acid ester type.
  • suitable liquid excipients such as greasy oils, paraffin oil or liquid polyethylene glycols or fatty acid esters of ethylene glycol or propylene glycol, it being likewise possible to add stabilizers and detergents, for example of the polyethylene sorbitan fatty acid ester type.
  • oral forms of administration are, for example, syrups prepared in the customary manner, which comprise the active ingredient, for example, in suspended form and in a concentration of about 5% to 20%, preferably about 10% or in a similar concentration which results in a suitable individual dose, for example, when 5 or 10 ml are measured out.
  • Other forms are, for example, also pulverulent or liquid concentrates for preparing of shakes, for example in milk. Such concentrates can also be packed in unit dose quantities.
  • compositions which can be used rectally, are, for example, suppositories that comprise a combination of the active ingredient with a suppository base.
  • Suitable suppository bases are, for example, naturally occurring or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.
  • compositions which are suitable for parenteral administration are aqueous solutions of an active ingredient in water-soluble form, for example of water-soluble salt, or aqueous injection suspensions, which comprise viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran, and if appropriate stabilizers.
  • the active ingredient can also be present here in the form of a lyophilisate, if appropriate together with excipients, and be dissolved before parenteral administration by addition of suitable solvents.
  • Solutions such as are used, for example, for parental administration can also be used as infusion solutions.
  • Preferred preservatives are, for example.
  • Antioxidants such as ascorbic acid, or microbicides, such as sorbic or benzoic acid.
  • Ointments are oil-in-water emulsions, which comprise not more than 70%, but preferably 20-50% of water or aqueous phase.
  • the fatty phase consists, in particular, hydrocarbons, for example vaseline, paraffin oil or hard paraffin's, which preferably comprise suitable hydroxy compounds, such as fatty alcohol's or esters thereof, for example cetyl alcohol or wool wax alcohols, such as wool wax, to improve the water-binding capacity.
  • Emulsifiers are corresponding lipophilic substances, such as sorbitan fatty acid esters (Spans), for example sorbitan oleate and/or sorbitan isostearate.
  • Additives to the aqueous phase are, for example, humectants, such as polyalcohols, for example glycerol, propylene glycol, sorbitol and/or polyethylene glycol, or preservatives and odoriferous substances.
  • humectants such as polyalcohols, for example glycerol, propylene glycol, sorbitol and/or polyethylene glycol, or preservatives and odoriferous substances.
  • Fatty ointments are anhydrous and comprise, as the base, in particular, hydrocarbons, for example paraffin, vaseline or paraffin oil, and furthermore naturally occurring or semi-synthetic fats, for example hydrogenated coconut-fatty acid triglycerides, or, preferably, hydrogenated oils, for example hydrogenated groundnut or castor oil, and furthermore fatty acid partial esters of glycerol, for example glycerol mono- and/or distearate, and for example, the fatty alcohols. They also contain emulsifiers and/or additives mentioned in connection with the ointments which increase uptake of water.
  • hydrocarbons for example paraffin, vaseline or paraffin oil
  • furthermore naturally occurring or semi-synthetic fats for example hydrogenated coconut-fatty acid triglycerides, or, preferably, hydrogenated oils, for example hydrogenated groundnut or castor oil, and furthermore fatty acid partial esters of glycerol, for example glycerol mono- and/
  • Creams are oil-in-water emulsions, which comprise more than 50% of water.
  • Oily bases used are, in particular, fatty alcohols, for example lauryl, cetyl or stearyl alcohols, fatty acids, for example palmitic or stearic acid, liquid to solid waxes, for example isopropyl myristate, wool wax or beeswax, and/or hydrocarbons, for example vaseline (petrolatum) or paraffin oil.
  • Emulsifiers are surface-active substances with predominantly hydrophilic properties, such as corresponding nonionic emulsifiers, for example fatty acid esters of polyalcohols or ethyleneoxy adducts thereof, such as polyglyceric acid fatty acid esters or polyethylene sorbitan fatty esters (Tweens), and furthermore polyoxyethylene fatty alcohol ethers or polyoxyethylene fatty acid esters, or corresponding ionic emulsifiers, such as alkali metal salts of fatty alcohol sulfates, for example sodium lauryl sulfate, sodium cetyl sulfate or sodium stearyl sulfate, which are usually used in the presence of fatty alcohols, for example cetyl stearyl alcohol or stearyl alcohol.
  • corresponding nonionic emulsifiers for example fatty acid esters of polyalcohols or ethyleneoxy adducts thereof, such as polyglyceric acid fatty acid esters or polyethylene
  • Additives to the aqueous phase are, inter alia, agents which prevent the creams from drying out, for example polyalcohols, such as glycerol, sorbitol, propylene glycol and/or polyethylene glycols, and furthermore preservatives and odoriferous substances.
  • polyalcohols such as glycerol, sorbitol, propylene glycol and/or polyethylene glycols, and furthermore preservatives and odoriferous substances.
  • Pastes are creams and ointments having secretion-absorbing powder constituents, such as metal oxides, for example titanium oxide or zinc oxide, and furthermore talc and/or aluminum silicates, which have the task of binding the moisture or secretions present.
  • secretion-absorbing powder constituents such as metal oxides, for example titanium oxide or zinc oxide, and furthermore talc and/or aluminum silicates, which have the task of binding the moisture or secretions present.
  • Foams are administered from pressurized containers and they are liquid oil-in-water emulsions present in aerosol form.
  • halogenated hydrocarbons such as chlorofluoro-lower alkanes, for example dichlorofluoromethane and dichlorotetrafluoroethane, or, preferably, non-halogenated gaseous hydrocarbons, air, N.sub.2 O, or carbon dioxide are used.
  • the oily phases used are, inter alia, those mentioned above for ointments and creams, and the additives mentioned there are likewise used.
  • Tinctures and solutions usually comprise an aqueous-ethanolic base to which, humectants for reducing evaporation, such as polyalcohols, for example glycerol, glycols and/or polyethylene glycol, and re-oiling substances, such as fatty acid esters with lower polyethylene glycols, i.e. lipophilic substances soluble in the aqueous mixture to substitute the fatty substances removed from the skin with the ethanol, and, if necessary, other excipients and additives, are admixed.
  • humectants for reducing evaporation such as polyalcohols, for example glycerol, glycols and/or polyethylene glycol
  • re-oiling substances such as fatty acid esters with lower polyethylene glycols, i.e. lipophilic substances soluble in the aqueous mixture to substitute the fatty substances removed from the skin with the ethanol, and, if necessary, other excipients and additives, are
  • the present disclosure also relates to a process or method for treatment of the disease states.
  • the compounds can be administered prophylactically or therapeutically as such or in the form of pharmaceutical compositions, preferably in an amount, which is effective against the diseases mentioned.
  • a warm-blooded animal for example a human, requiring such treatment, the compounds are used, in particular, in the form of pharmaceutical composition.
  • a daily dose of about 0.1 to about 5 g, preferably 0.5 g to about 2 g, of a compound of the present disclosure is administered here for a body weight of about 70 kg.
  • the present disclosure provides a method of treating, preventing, or ameliorating at least one symptom of, a disease or disorder in a subject.
  • the method comprising administering an effective amount of the peptide-oligourea compound or foldamer of the present disclosure or the pharmaceutical composition of the present disclosure to a subject in need thereof, wherein the peptide or pharmaceutical composition is effective for treating, preventing, or ameliorating at least one symptom of the disease or disorder.
  • the description provides methods of treating a disease or disorder or ameliorating the effects of the same comprising the steps of administering to an individual in need thereof, a composition comprising an effective amount of a compound as described herein, and a pharmaceutically acceptable carrier or excipient, wherein the composition is effective for treating, preventing or ameliorating the effects of the disease or disorder.
  • the present disclosure provides a method of treating, preventing, or ameliorating at least one symptom of, a disease or disorder in a subject, the method comprising administering a composition comprising an effective amount of a chimeric compound or foldamer to a subject in need thereof, wherein the chimeric compound or foldamer is a GLP-1 analogue having at least one amino acid substituted with a residue having a urea, a thiourea, or a guanidine moiety resulting in an N, N'-linked urea, thiourea, or guanidine bridging unit, respectively, wherein the disease or disorder is selected from the group consisting of diabetes, obesity, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), a neurodegenerative or cognitive disease or disorder, heart disease, microvascular disease, atherosclerosis or cardiovascular disease, myocardial infarction, strokes, or a combination thereof, and wherein the composition
  • NAFLD non-
  • the parent (i.e., that "natural") peptide is a class B GPCR ligand or derivative thereof (e.g., lixisenatide, exenatide, semaglutide, liraglutide, albiglutide, dulaglutide, derivatives thereof, and combinations thereof).
  • the disease or disorder is selected from the group consisting of diabetes (such as diabetes mellitus type 1 or diabetes mellitus type 2), a neurodegenerative disease or disorder (such as peripheral neuropathy, Alzheimer's disease, Parkinson's disease, Fluntington's disease, amyotrophic sclerosis, multiple sclerosis, traumatic brain injury, or spinal cord injury), or a combination thereof.
  • diabetes such as diabetes mellitus type 1 or diabetes mellitus type 2
  • a neurodegenerative disease or disorder such as peripheral neuropathy, Alzheimer's disease, Parkinson's disease, Fluntington's disease, amyotrophic sclerosis, multiple sclerosis, traumatic brain injury, or spinal cord injury
  • the compounds described above are used for the manufacture of a medication for use in the treatment of a disease, disorder or condition.
  • disease, disorder or condition means, in the context of the present disclosure, any human or animal disease affecting one or more organs.
  • Exemplary diseases include, but are not limited to, rheumatoid arthritis, osteoarthritis, juvenile chronic arthritis, Lyme arthritis, psoriatic arthritis, reactive arthritis, spondyloarthropathy, systemic lupus erythematosus, Crohn's disease, ulcerative colitis, inflammatory bowel disease, insulin dependent diabetes mellitus, thyroiditis, asthma, allergic diseases, psoriasis, dermatitis scleroderma, atopic dermatitis, graft versus host disease, organ transplant rejection, acute or chronic immune disease associated with organ transplantation, sarcoidosis, atherosclerosis, disseminated intravascular coagulation, Kawasaki's disease, Grave's disease, nephrotic syndrome, chronic fatigue syndrome, Wegener's granulomatosis, Henoch-Schoenlein purpurea, microscopic vasculitis of the kidneys, chronic active hepatitis, uveitis, septic shock,
  • the methods herein include administering to the subject (including a subject identified as in need of such treatment) an effective amount of a compound described herein, or a composition described herein to produce a desired effect. Identifying a subject in need of such treatment can be in the judgment of the subject or a health care professional and can be subjective (e.g., opinion) or objective (e.g., measurable by a test or diagnostic method).
  • the therapeutic methods of the present disclosure which include prophylactic treatment, in general comprise administration of a therapeutically effective amount of at least one of the compounds herein, such as a compound of the formulae herein to a subject (e.g., animal, human) in need thereof, including a mammal, particularly a human.
  • Such treatment will be suita bly administered to subjects, particularly humans, suffering from, having, susceptible to, or at risk for a disease, disorder, or symptom thereof. Determination of those subjects "at risk” can be made by a ny objective or subjective determination by a diagnostic test or opinion of a subject or health care provider (e.g., genetic test, enzyme or protein marker, Marker (as defined herein), family history, and the like).
  • a diagnostic test or opinion of a subject or health care provider e.g., genetic test, enzyme or protein marker, Marker (as defined herein), family history, and the like.
  • the present description provides methods of making and using the compounds as described herein.
  • the compounds as described herein can be used as a diagnostic agent or a therapeutic agent for the treatment of a disease or condition.
  • the present disclosure provides a method of monitoring treatment progress.
  • the method includes the step of determining a level of diagnostic marker (Marker) (e.g., any target delineated herein modulated by a compound herein, a protein or indicator thereof, etc.) or diagnostic measurement (e.g., screen, assay) in a subject suffering from or susceptible to a disorder or symptoms thereof associated with protein-expression related disease (including misfolding), in which the subject has been administered a therapeutic amount of a compound herein sufficient to treat the disease, disorder, condition, or symptoms thereof.
  • the level of Ma rker determined in the method can be compared to known levels of Marker in either healthy normal controls or in other afflicted patients to establish the subject's disease status.
  • a second level of Marker in the subject is determined at a time point later than the determination of the first level, and the two levels are compared to monitor the course of disease or the efficacy of the therapy.
  • a pre-treatment level of Marker in the subject is determined prior to beginning treatment according to the present disclosure; this pre treatment level of Marker can then be compared to the level of Marker in the subject after the treatment commences, to determine the efficacy of the treatment.
  • the active compound is included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutically effective amount for the desired indication, without causing serious toxic effects in the patient treated.
  • a preferred dose of the active compound for all of the herein-mentioned conditions is in the range from about 10 ng/kg to 300 mg/kg, preferably 0.1 to 100 mg/kg per day, more generally 0.5 to about 25 mg per kilogram body weight of the recipient/patient per day.
  • a typical topical dosage will range from 0.01-5% wt/wt in a suitable carrier.
  • the compound may be conveniently administered in any suitable unit dosage form, including but not limited to one containing less than 1 mg, 1 mg to 3000 mg, preferably 5 to 500 mg of active ingredient per unit dosage form.
  • An oral dosage of about 25-250 mg is often convenient.
  • the active ingredient is preferably administered to achieve peak plasma concentrations of the active compound of about 0.00001-30 mM, preferably about 0.1-30 mM.
  • This may be achieved, for example, by the intravenous injection of a solution or formulation of the active ingredient, optionally in saline, or an aqueous medium or administered as a bolus of the active ingredient. Oral administration is also appropriate to generate effective plasma concentrations of active agent.
  • concentration of active compound in the drug composition will depend on absorption, distribution, inactivation, and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated.
  • compositions should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition.
  • the active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at varying intervals of time.
  • the present description provides methods of making and using the compounds of the present disclosure.
  • the description provides a method of making a compound of the present disclosure comprising synthesizing an oligomer of residues comprising at least one or a plurality of N, N'-linked urea bridging unit, wherein the oligomer is coupled to at least one amino acid of a peptide backbone, wherein the peptide- oligourea compound has at least one non-consecutive urea amino acid in the backbone.
  • the peptide does not have more than one consecutive urea amino acid in the backbone.
  • the urea amino acid is an N-2-ethylaminocarbamoyl residue.
  • the description provides a method of synthesizing a compound comprising the steps of:
  • polypeptide or fragment of step (a) are replaced by m urea amino acid residues selected from the group consisting of / ⁇ /-2-aminoethylcarbamoyl residues and acyclic y-amino acid residues, and m is 1 or more, wherein at least one urea amino acid cannot be bound to another urea amino acid;
  • the synthetic polypeptide has a length of from about 5 or 6 residues to about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 or more residues (including intermediate values) and comprises at least 1 residue selected from the group consisting of L/-2- aminoethylcarbamoyl residues and acyclic y-amino acid residues.
  • the description provides methods of improving the pharmacologic effect of a peptide or peptidomimetic comprising, e.g., substituting one or more non-consecutive amino acids of the peptide or peptidomimetic with at least one residue selected from the group consisting of substituted or unsubstituted N-2-aminoethylcarbamoyl residue, 0-amino acid residue, substituted or unsubstituted N-(2-aminoethyl)carbamothioyl residues, substituted or unsubstituted N-(2-aminoethyl)formamidinyl residues, substituted or unsubstituted 2-aminoethanoxycarbonyl, and a combination thereof.
  • the compound is a peptide or peptide derivative, analog or mimetic.
  • the compound is an incretin or derivative thereof.
  • the incretin is selected from the group consisting of lixisenatide, exenatide, semaglutide, liraglutide, albiglutide, dulaglutide, and combinations thereof.
  • the present disclosure provides a method of improving the pharmacologic effect of a peptide or a peptidomimetic.
  • the method comprises: substituting a plurality of amino acids of the peptide or peptidomimetic with a residue selected from an aminourea, a thiourea, and a guanidine, wherein at least one non-consecutive amino acid has been monosubstituted by an aminourea, a thiourea, or a guanidine.
  • the peptide is at least one member selected from the group consisting of compound 2-13, 15, 17, 18, 20-65, 67-70, 72-81, and combinations thereof.
  • the peptide is a class B GPCR ligand or derivative thereof.
  • the class B GPCR ligand or derivative thereof may be selected from the group consisting of lixisenatide, lixisenatixe, exenatide, semaglutide, liraglutide, albiglutide, dulaglutide, derivatives thereof, and combinations thereof.
  • the peptide is an incretin or a derivative thereof.
  • the incretin or derivative thereof may be selected from the group consisting of lixisenatide, exenatide, semaglutide, liraglutide, albiglutide, dulaglutide, derivatives thereof, and combinations thereof.
  • Incretins are a group of metabolic hormones that stimulate a decrease in blood glucose levels. Incretins do so by causing an increase in the amount of insulin released from pancreatic beta cells of the islets of Langerhans after eating, before blood glucose levels become elevated. They also slow the rate of absorption of nutrients into the blood stream by reducing gastric emptying and may directly reduce food intake. They also inhibit glucagon release from the alpha cells of the islets of Langerhans.
  • GLP-1 glucagon-like peptide-1
  • GIP gastric inhibitory peptide
  • DPP-4 dipeptidyl peptidase-4
  • GLP-1 and GIP are members of the glucagon peptide superfamily.
  • GLP-1 (7-36) amide is not very useful for treatment of type 2 diabetes mellitus, since it must be administered by continuous subcutaneous infusion.
  • Several long-lasting analogs having insulinotropic activity have been developed, and three, exenatide (Byetta) and liraglutide (Victoza), plus exenatide extended-release (Bydureon), have been approved for use in the U.S.
  • the main disadvantage of these GLP-1 analogs is they must be administered by subcutaneous injection.
  • GLP-1 analogs include semaglutide (Ozempic by Novo Nordisk), lixisenatide (Lyxumia by Sanofi), exenatide (Byetta, Bydureon), liraglutide (Victoza), albiglutide (Tanzeum), and dulaglutide (by Lili).
  • Lixisenatide (trade name Lyxumia) is a once-daily injectable GLP-1 receptor agonist for the treatment of diabetes, discovered by Zealand Pharma A/S of Denmark and licensed and developed by Sanofi. Lixisenatide was accepted for review by the US FDA on February 19, 2013, and approved by the European Commission on February 1, 2013. On September 12, 2013, Sanofi delayed the approval process in the US, citing internal data from a cardiovascular risk study. The drug will likely be resubmitted for approval in 2015.
  • Lixisenatide has been described as "des-38-proline-exendin-4 (Heloderma suspectum)-(l- 39)-peptidylpenta-L-lysyl-L-lysinamide", meaning it is derived from the first 39 amino acids in the sequence of the peptide exendin-4, found in the Gila monster (Heloderma suspectum), omitting proline at position 38 and adding six lysine residues.
  • Exenatide (marketed as Byetta, Bydureon) is a glucagon-like peptide-1 agonist (GLP-1 agonist) medication, belonging to the group of incretin mimetics, approved in April 2005 for the treatment of diabetes mellitus type 2.
  • GLP-1 agonist glucagon-like peptide-1 agonist
  • Exenatide in its Byetta form is administered as a subcutaneous injection (under the skin) of the abdomen, thigh, or arm, any time within the 60 minutes before the first and last meal of the day.
  • a once-weekly injection has been approved as of January 27, 2012 under the trademark Bydureon. It is manufactured by Amylin Pharmaceuticals and commercialized by AstraZeneca.
  • Exenatide is a synthetic version of exendin-4, a hormone found in the saliva of the Gila monster. It displays biological properties similar to human glucagon-like peptide-1 (GLP-1), a regulator of glucose metabolism and insulin secretion. According to the package insert, exenatide enhances glucose-dependent insulin secretion by the pancreatic beta-cell, suppresses inappropriately elevated glucagon secretion, and slows gastric emptying, although the mechanism of action is still under study.
  • GLP-1 human glucagon-like peptide-1
  • Exenatide is a 39-amino-acid peptide, an insulin secretagogue, with glucoregulatory effects. Exenatide was approved by the FDA on April 28, 2005 for patients whose diabetes was not well-controlled on other oral medication. The medication is injected subcutaneously twice per day using a filled pen-like device (Byetta), or on a weekly basis with either a pen-like device or conventional syringe (Bydureon).
  • GLP-1 and GIP glucose-dependent insulinotropic peptide
  • GLP-1 and GIP stimulate insulin secretion from the beta cells of the islets of Langerhans in the pancreas.
  • GLP-1 causes insulin secretion in the diabetic state; however, GLP-1 itself is ineffective as a clinical treatment for diabetes as it has a very short half-life in vivo.
  • Exenatide bears a 50% amino acid homology to GLP-1 and it has a longer half-life in vivo. Thus, it was tested for its ability to stimulate insulin secretion and lower blood glucose in mammals, and was found to be effective in the diabetic state. In studies on rodents, it has also been shown to increase the number of beta cells in the pancreas.
  • exenatide is produced by direct chemical synthesis. Historically, exenatide was discovered as Exendin-4, a protein naturally secreted in the saliva and concentrated in the tail of the Gila monster. Exendin-4 shares extensive homology and function with mammalian GLP-1, but has a therapeutic advantage in its resistance to degradation by DPP-IV (which breaks down GLP-1 in mammals) therefore allowing for a longer pharmacological half-life.
  • the biochemical characteristics of Exendin-4 enabled consideration and development of exenatide as a diabetes mellitus treatment strategy. Given this history, exenatide is sometimes referred to as "lizard spit". Subsequent clinical testing led to the discovery of the also desirable glucagon and appetite-suppressant effects.
  • exenatide raises insulin levels quickly (within about ten minutes of administration) with the insulin levels subsiding substantially over the next hour or two.
  • a dose taken after meals has a much smaller effect on blood sugar than one taken beforehand. The effects on blood sugar diminish after six to eight hours.
  • the medicine is available in two doses: 5 meg. and 10 meg. Treatment often begins with the 5 meg. dosage, which is increased if adverse effects are not significant.
  • Its once weekly Bydureon form is unaffected by the time between the injection and when meals are taken. Bydureon has the advantage of providing 24- hour coverage for blood sugar lowering, while Byetta has the advantage of providing better control of the blood sugar spike that occurs right after eating.
  • the autoinjector must be stored in a refrigerator between 2 °C (36 °F) and 8 °C (46 °F) before first use, and then at a temperature between 2 °C (36 °F) and 25 °C (77 °F). In hot weather, therefore, they should be refrigerated. Pens contain sixty doses designed to be used twice a day for 30 days. Exenatide received US Patent 5,424,286 which was filed May 24, 1993.
  • Exenatide is believed to facilitate glucose control in at least five ways:l. Exenatide augments pancreas response (i.e. increases insulin secretion) in response to eating meals; the result is the release of a higher, more appropriate amount of insulin that helps lower the rise in blood sugar from eating. Once blood sugar levels decrease closer to normal values, the pancreas response to produce insulin is reduced; other drugs (like injectable insulin) are effective at lowering blood sugar, but can "overshoot" their target and cause blood sugar to become too low, resulting in the dangerous condition of hypoglycemia.
  • Exenatide reduces liver fat content. Fat accumulation in the liver or nonalcoholic fatty liver disease (NAFLD) is strongly related with several metabolic disorders, in particular low H DL cholesterol and high triglycerides, present in patients with type 2 diabetes. It became apparent that exenatide reduced liver fat in mice and more recently in man.
  • NASH nonalcoholic fatty liver disease
  • Exenatide is approved "as adjunctive therapy to improve glycemic control in patients with type 2 diabetes mellitus who are taking metformin, a biguanide, or a combination of metformin and a sulfonylurea, but have not achieved adequate glycemic control.” It has now been approved for use with thiazolidinediones such as pioglitazone. In 2011, Byetta was approved by the FDA for use as a substitute for mealtime insulin.
  • exenatide is indicated to improve glycemic control in patients with type 2 diabetes who are taking metformin, a sulfonylurea, thiazolidinediones, or a combination of metformin and sulfonylurea or thiazolidinediones, but who have not been able to achieve adequate control of blood glucose.
  • Liraglutide (NN2211) is a long-acting glucagon-like peptide-1 receptor agonist, binding to the same receptors as does the endogenous metabolic hormone GLP-1 that stimulates insulin secretion. Marketed under the brand name Victoza, it is an injectable drug developed by Novo Nordisk for the treatment of type 2 diabetes. In 2015, Novo Nordisk began marketing it in the U.S. under the brand name Saxenda as a treatment for obesity in adults with at least one weight-related comorbid condition.
  • Liraglutide improves control of blood glucose. It reduces meal-related hyperglycemia (for 24 hours after administration) by increasing insulin secretion (only) when required by increasing glucose levels, delaying gastric emptying, and suppressing prandial glucagon secretion. In common to various degrees with other GLP-1 receptor agonists, liraglutide has advantages over more traditional therapies for type 2 diabetes: it acts in a glucose-dependent manner, meaning it will stimulate insulin secretion only when blood glucose levels are higher than normal, preventing "overshoot".
  • Liraglutide is an acylated glucagon-like peptide-1 (GLP-1) agonist, derived from human GLP-l-(7-37), a less common form of endogenous GLP-1.
  • GLP-1 acylated glucagon-like peptide-1
  • Liraglutide leads to insulin release in pancreatic beta cells in the presence of elevated blood glucose. This insulin secretion subsides as glucose concentrations decrease and approach euglycemia (normal blood glucose level). It also decreases glucagon secretion in a glucose- dependent manner and delays gastric emptying. Unlike endogenous GLP-1, liraglutide is stable against metabolic degradation by peptidases, with a plasma half-life of 13 hours.
  • Endogenous GLP-1 has a plasma half-life of 1.5-2 minutes due to degradation by the ubiquitous enzymes, dipeptidyl peptidase-4 (DPP4) and neutral endopeptidases (NEP).
  • DPP4 dipeptidyl peptidase-4
  • NEP neutral endopeptidases
  • the half-life after intramuscular injection is approximately half an hour, so even administered this way, it has limited use as a therapeutic agent.
  • the metabolically active forms of GLP-1 are the endogenous GLP-l-(7-36)NH 2 and the more rare GLP-l-(7-37).
  • liraglutide is achieved by attaching a fatty acid molecule at one position of the GLP-l-(7-37) molecule, enabling it to both self-associate and bind to albumin within the subcutaneous tissue and bloodstream.
  • the active GLP- 1 is then released from albumin at a slow, consistent rate.
  • Albumin binding also results in slower degradation and reduced renal elimination compared to that of GLP-l-(7-37).
  • Albiglutide (tradenames Eperzan and Tanzeum) is a glucagon-like peptide-1 agonist (GLP-1 agonist) drug marketed by GlaxoSmithKline (GSK) for treatment of type 2 diabetes.
  • Dulaglutide is a glucagon-like peptide 1 receptor agonist (GLP-1 agonist) for the treatment of type 2 diabetes that can be used once weekly.
  • GLP-1 is a hormone that is involved in the normalization of level of glucose in blood (glycemia).
  • Dulaglutide binds to glucagon-like peptide 1 receptors, slowing gastric emptying and increases insulin secretion by pancreatic Beta cells. Simultaneously the compound reduces the elevated glucagon secretion by inhibiting alpha cells of the pancreas, which is known to be inappropriate in the diabetic patient.
  • GLP-1 is normally secreted by L cells of the gastrointestinal mucosa in response to a meal.
  • the compound is indicated for adults with type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycemic control.
  • Dulaglutide is not indicated in the treatment of subjects with type 1 diabetes mellitus or patients with diabetic ketoacidosis.
  • Dulaglutide can be used either stand-alone or in combination with other medicines for type 2 diabetes, in particular metformin, sulfonylureas, thiazolidinediones, and insulin taken concomitantly with meals.
  • oligomeric backbones consisting of N,N'- linked urea bridging units (see Figure 1A) possess a remarkable propensity to fold into helical secondary structures in organic solvents and showed promise for interaction with biologically relevant targets. Compared to alpha-peptides, helix stabilization in oligoureas is promoted by the presence of additional backbone conformational restriction and H-bond donor sites.
  • a representative oligourea with antimicrobial properties (compound la, Figure IB) is also shown to illustrate the diversity of side chains that is accessible in oligoureas.
  • compound la has been found to maintain a helical conformation in aqueous environment illustrating the potential of oligoureas as bioactive compounds. See : P. Claudon, A. Violette, K. Lamour, M. Decossas, S. Fournel, B. Fleurtault, J. Godet, Y. Mely, B. Jamart-Gregoire, M.-C. Averlant-Petit, J.-P. Briand, G. Duportail, FI. Monteil, G. Guichard, Angew. Chem. Int. Ed. Engl. 2010, 49, 333-336)2.
  • chimeric foldamers compounds having a polypeptide portion contiguous with or linked to oligomers of amino acids having an N, N'-linked urea bridging unit
  • the chimeric compounds previously described have regular and persistent helical conformations and improved helix stability.
  • chimeric foldamers can adopt desired secondary structures similar to native peptides, including, e.g., linear, cyclic or helicoidal structures
  • the inventors decided to examine if non-consecutive substitutions could be used to prepare peptide-oligourea compounds that could serve as, for example, receptor ligands, effector molecules, agonists, antagonists, modulators of protein-protein interactions, orga nocatalysts or enzymes.
  • Oligoureas can be derived from building blocks with any desired amino acid side chain.
  • the insoluble product was filtered off and washed with methanol. The filtrate and washings were combined and the solvent was removed under vacuum. The mixture was dissolved in NaHCOs and CH2CI2. The organic layer was washed with saturated NaHC03, dried over Na2S04, and concentrated under reduced pressure. The resulting oil was dissolved in concentrated HCI (pH 2-3) and the aqueous layer was washed with Et 2 0 a nd EtOAc, the aqueous layer was then basified with K2CO3 until pH 8. The compound was extracted from the aqueous layer with CH2CI2 (three times) and the organic phases were combined, dried over Na2S04 and concentrated under reduced pressure.
  • the desired activated building block was crystallised in a mixture of Et 2 0 and pentane and recovered by filtration [00332]
  • An exemplary procedure for Boc removal and peptide coupling in the synthesis of peptide- oligourea compounds of the present disclosure is as follows: the N- Boc protected oligomer was dissolved in TFA at 0°C under N2. After stirring for 1 hour, TFA was removed in vacuo and coevaporated with cyclohexane.
  • the a-amino acid (0.95eq.) was dissolved in a small quantity of dimethylformamide with BOP (0.95 eq.) and cooled to 0°C under N2, the TFA salt and DIPEA (3.0 eq.) were added and the reaction was allowed to stir over night.
  • the mixture was diluted with NaFIC03 and EtOAc.
  • the organic layer was washed with NaHCOs, KHSO4 and brine, dried over Na2S04, and concentrated under reduced pressure.
  • the resulting solid was column purified (CH 2 CI 2 /MeOH, 2%).
  • 0TC6 cells were suspended in Hank's Balanced Salt Solution (HBSS) buffer (Invitrogen) complemented with 20 mM HEPES (4-(2-hydroxyethyl)-l-piperazineethanesulfonic acid) (pH 7.4) and 500 mM IBMX (3- lsobutyl-1-methylxanthine), then distributed in microplates at a density of 1.5xl0 4 cells/well and incubated for 10 minutes at room temperature in the presence of HBSS (basal control), the test compound or the reference agonist. For stimulated control measurement, separate assay wells contain 10 nM GLP-l(7-37) were utilized.
  • HBSS Hank's Balanced Salt Solution
  • D2-labeled cAMP fluorescence acceptor
  • fluorescence donor anti-cAMP antibody labeled with europium cryptate
  • each compound was evaluated in duplicate on both (MDM2 or MDMX) / p53 interaction and on a positive TR-FRET control protein in a 384-well reaction plate.
  • the final compound concentrations in these assays were 10 mM, 1 and 0.1 mM in 2.5 % DMSO.
  • the reference compound Nutlin-3 is integrated in the compound daughter plate and was used under the same conditions.
  • HTRF Homogeneous Time-Resolved Fluorescence
  • TR-FRET time resolved fluorescence energy transfer
  • Many compounds and proteins present in biological fluids or serum are naturally fluorescent, and the use of conventional, prompt fluorescence leads to serious limitations in assay sensitivity.
  • the use of long-lived fluorophore combined with time- resolved detection minimizes prompt fluorescence interference.
  • the GST-Flag-Mdm2 (AA1-188 ; Gl:4505136) or GST-Flag-MdmX ( AA1-174 ; Gl:88702790) / THX-HIS-p53 (AA1-83 ; Gl:8400737) interaction was detected by an optimized HTRF assay.
  • Specific anti-GST antibody bearing a fluorescence donor (EuK) and an anti-His antibody bearing a fluorescence acceptor (XL665) recognize tags on each fusion protein.
  • the interaction between both purified proteins was detected by fluorescence transfer (excitation at 337 nm, emission at 665 nm). The emission at 620 nm occurs regardless of the interaction, and allows for normalizing the assay. Disruption of the protein-protein interaction suppresses the signal.
  • a measure of the HTRF signal obtained for the protein-protein interaction is brought by:
  • ratio is the 665/620 fluorescence ratio
  • sample is the signal in presence of HTRF antibodies
  • background denotes the HTRF antibodies in buffer only.
  • raw data files indicate the fluorescence signal at 620 and 665 nm and the 665/620 fluorescence ratio of the two replicates.
  • the analysis files provide Inhibition % of the interaction for each replicate, and compute the mean value and standard deviation for each compound.
  • Enzymatic Degradation - Chymotrypsin and Trypsin Stock solutions of the compounds were prepared at a concentration of 400 mM in a solution of 50 mM HEPES buffer, 50 mM NaCI, 0.05% Tween-80, pH 8.0. Stock solution of the chymotrypsin or trypsin was prepared at a concentration of 250 mg/mL in water. Stability of compounds to chymotrypsin was assessed by conducting a protease reaction in a 96-well plates at room temperature.
  • PBS buffer solution (10 mM sodium phosphate, 0.14 M NaCI) was prepared as follows: Solution A (4.75 mL of 0.2 M NahhPC HbO), solution B (20.25 mL of 0.2 M Na2HP04-H20), NaCI (4.5 g), and H2O (25 mL) were stirred for 15 min at room temperature and diluted tenfold with H2O. The pH was adjusted either with NaOH (1 M) or with HCI (1 M) prior to use. A solution of the substrate in PBS buffer (pH 7.2, 0.01 M) and a solution of the required amount of enzyme, were mixed and incubated at 25°C for 4 hours. Degradation was stopped with concentrated AcOH, and buffer solution was added so that the total volume reached 150 pL.
  • Carboxypeptidase A (EC 3.4.17.1) from bovine pancreas (Fluka), milky suspension, stock solution in PBS buffer (pH 7.5, 0.01 M).
  • PBS buffer pH 7.5, 0.01 M
  • stock solutions of the peptidic substrate and the enzyme were made using PBS buffer solution.
  • the enzyme concentrations of the stock solutions were selected such that the standard substrates were totally degraded after a maximum of 15 min (ratio 2[enzyme] : 100[substrate]).
  • PBS buffer solution (10 mM sodium phosphate, 0.14 M NaCI) was prepared as follows: Solution A (4.75 mL of 0.2 M Na ⁇ PC ⁇ O), solution B (20.25 mL of 0.2 M Na2HP04-H20), NaCI (4.5 g) and H20 (25 mL) were stirred for 15 min at room temperature and diluted tenfold with H2O. The pH was adjusted either with NaOH (1 M) or with HCI (1 M) prior to use. A solution of the substrate in PBS buffer (pH 7.5, 0.01 M) and a solution of the required amount of enzyme, were mixed and incubated at 25°C for 4 hours. Degradation was stopped with concentrated AcOH, and buffer solution was added so that the total volume reached 150 pL.
  • Solubility A solution of 3 mg/ml of glucagon (or analog) was prepared in a 0.01M HCI solution. Then 0.1 ml of the stock solution was diluted to 1 ml with HCI (0.01M) and the UV absorbance measured (to 280 nm) with nanodrop UV spectrometer. The pH of the remaining stock solution was adjusted to 7 using Na2HPC>4, and the solution was incubated overnight at 4°C. The solution was then centrifuged three times (5 minutes, 4000 rotations per minute), 0.1 ml of the supernatant was removed and diluted to 1 ml with HCI solution (0.01M).
  • mice were housed in ventilated and enriched housing cages (310 x 125 x 127 mm 3 ) throughout the experimental phase.
  • the mice were housed in groups of 5 animals during the whole study, on a normal 12 hours light cycle (at 08:00 pm lights off), 22 ⁇ 2 °C and 50 ⁇ 10 % relative humidity.
  • the mice were acclimated for 5-days.
  • a standard chow diet (RM1 (E) 801492, SDS) and tap water were provided ad libitum.
  • IPGTT Intraperitoneal Glucose Tolerance Testing
  • Table 1 shows the EC50 of GLP-1 antagonists compounds 1-8, 12-15, 25-28, 43-50, 66-69, 72, and 73, which have the amino acid sequence of SEQ ID NOS: 1-8, 12-15, 25-28, 43-50, 66-69, 72, and 73, respectively. It was surprisingly discovered, as shown in Table 1, that the monosubstitution of one or more amino acids by an amino urea in a GLP-1 antagonist generally maintained functional activity.
  • Table 3 shows the EC50 of glucagon receptor agonists compounds 16, 34-36, 51-53, and 55-65, which have the amino acid sequence of SEQ ID NOS: 16, 34-36, 51-53, and 55-65, respectively. It was surprisingly discovered, as shown in Table 3, that the monosubstitution of one or more amino acids by an amino urea in a glucagon receptor agonist generally maintained functional activity.
  • GLP-1 Enzymatic Stability. It was surprising that the monosubstitution of one or more amino acids by an amino urea improved the stability of peptides toward enzymatic degradation, while maintaining a good affinity with its receptor.
  • Glucagon Solubility Compounds 16, and 51-65, which have the amino acid sequence of SEQ ID NO: 16 and 51-65, were examined for solubility. It was surprisingly discovered that the monosubstitution of one or more amino acids by an amino urea in glucagon had the general effect of improving its solubility. Table 5 illustrates the improvement of glucagon analog solubility which moderated bioactivities.
  • FIG. 3A, 3B, 3C, 4A, 4B, 4C, and 5 demonstrate the comparison of exemplary peptide compounds as described herein with exenatide, or lixisenatide.
  • Figures 3A and 4A show the effect compounds URK-394 (SEQ ID NO: 72) and URK-434 (SEQ ID NO: 15) has on blood glucose before and after IV treatment, relative to vehicle and exenatide.
  • Figures 3B and 4B show the effect compounds URK-394, URK-434, and URK-468 (SEQ ID NO: 67) has on blood glucose before and after glucose load, relative to vehicle and exenatide.
  • Figures 3C and 4 C show that the area under the curve (AUC) for the same.
  • Figure 5 compares several exemplary compounds as described herein with exenatide.
  • Figure 7 illustrates an alignment of URK-479 (SEQ ID NO: 97), URK-468 (SEQ ID NO: 67), URK-470 (SEQ ID NO: 73), URK-434 (SEQ ID NO: 15), URK-526 (SEQ ID NO: 68), URK-280 (SEQ ID NO: 69), and URK-527 (SEQ ID NO: 74) with Exendin-4 (SEQ ID NO: 71).
  • mice treated with vehicle or receiving the FXR agonist obeticholic acid (OCA) in diet were assessed in parallel.
  • Compound 77 reduced liver damages induced by the diet in a dose dependent manner, more efficiently that the benchmark drug OCA. This observation was evidenced by a significant reduction of the histological NAS score, as well as a strong tendency to reduction of the hepatic transaminases, liver lipids and the inflammatory and fibrotic markers.
  • compound 77 revealed also significant anti-diabetic and anti-obesogenic properties. Taken together, these observations show compound 77 may be utilized to protect from diet-induced NASH progression in, e.g., a weekly dose administration protocol.
  • Non-alcoholic fatty liver disease is the most common liver disorder in industrialized countries.
  • the prevalence of NAFLD shows a dramatic acceleration this last decade to reach about 30% in general population.
  • Two phenotypic subgroups can be observed within the NAFLD patients: the non-alcoholic fatty liver (NAFL) patients characterized by simple steatosis; and the non-alcoholic steatohepatitis (NASH) patients presenting liver inflammation, hepatocyte injury (ballooning) that progress to fibrosis, cirrhosis and finally to hepatocellular carcinoma.
  • NASH non-alcoholic fatty liver disease
  • GLP-1 hormone belongs to the incretin group of proteins secreted by the L-cells in the distal ileum and proximal colon.
  • GLP-1 regulates several downstream signaling pathways dependent or not from the specific GLP-1 receptor.
  • GLP-1 stimulates the b-cells proliferation and insulin secretion by the pancreas, delays the gastric emptying, suppresses appetite, decreases the liver glucose production and improve the peripheral insulin sensitivity.
  • GLP-1 receptor agonists in the treatment of type 2 diabetes mellitus.
  • GLP-1 stimulates the glucose-induced insulin secretion, by rendering pancreatic b-cells glucose sensitive.
  • GLP-1 has no effect on this cell type.
  • GLP-1 agonists demonstrated also beneficial effects in reducing the NASH-score and body weight of treated patients.
  • DPP-4 dipeptidyl peptidase 4
  • these synthetic GLP-1 analogues are tailored to resist this rapid inactivation.
  • the main side effects of GLP-1 analogues observed in clinical trials, concern the gastrointestinal tract that include diarrhea, nausea, and vomiting. Therefore, one challenge of the currently designed GLP-1 analogues is to lengthened their half-life known to reduce the adverse effects as well as the perceptions of treatment burdens by the patients.
  • A2 Coupling of Fmoc-amino acid.
  • N- Fmoc-a amino acid (5 equiv relative to the resin loading) were coupled with PyBOP (5 equiv relative to the resin loading) and N,N- diisopropylethylamine (DIEA) (10 equiv relative to the resin loading) as coupling reagent using the standard liberty blue methods (J.M. Collins, K. A. Porter, S. K. Singh, G. S. Vanier, Org. Lett. 2014, 16, 940-943).
  • A3 Coupling of activated N3-building bloc.
  • the activated monomer (3 equiv relative to the resin loading) was coupled twice using DIEA (10 equiv relative to the resin loading) under microwave irradiation (70°C, 50W, 20 min) in DMF (4 mL).
  • A4 Reduction of azide group. The reduction of the azido group was performed twice in a mixture of l,4-dioxane/H 2 0 (7:3 v/v) (5 mL) with a 1M PMe3 solution in THF (10 equiv relative to the resin loading) under microwave irradiation (50°C, 50W, 30 minutes).
  • A5 Side chain synthesis.
  • the resin was transferred in a 10 mL syringe, 5 mL of dichloromethane (DCM) was added and the Alloc group was removed using Pd(Pfi3)4 (30 mg, 0.25 equiv relative to the resin loading) and phenylsilane (135 pL, 1.1 equiv relative to the resin loading) at room temperature for 45 minutes.
  • DCM dichloromethane
  • the resin was washed with DMF (2x) and DCM (3x), then DCM (5 mL) was added and the palmitoyl chloride (152 pL, 5 equiv relative to the resin loading), and DIEA (88 pL, 5 equiv relative to the resin loading) were loaded on the resin and it was shaken for 2 hours at room temperature.
  • A6 Cleavage from the resin. After completion of the synthesis, the resin was transferred into a syringe with a frit, and washed three times with DMF, three times with CH 2 CI 2 and three times with Et 2 0. Cleavage from the resin was performed using 95% TFA with 2.5% triisopropylsilane and 2.5% water (3 mL). After 2 hours, the resin was filtered and discarded. Diethyl ether was added to precipitate the oligomer and the solid was triturated and filtrated.
  • A7 Purification and characterization. Analytical RP-HPLC analyses were performed on a Dionex U3000SD using a Macherey-Nagel Nucleodur C18ec column (4 x 100 mm, 3 pm) at a flow rate of 1 mL/minute with UV detection at 200 nm. The mobile phase was composed of 0.1% (v/v) TFA-H 2 O (Solvent A) and 0.1% (v/v) TFA-CH 3 CN (solvent B).
  • LC-MS analyses were carried out on a UHPLC (Agilent 1290 Infinity) coupled to a ESI -MS Tof (Agilent 6230 ESI).
  • Electrospray ionization mass spectrometry (ESI-MS) experiments were performed on an Agilent 6560 DTIMS-Q-TOF spectrometer (Agilent Technologies, Santa Clara, CA), with the dual-ESI source operated in positive ion mode.
  • the cells were suspended in cell culture media (Eagle's minimal essential medium IX + GlutaMAX (Gibco 31966-021)) complemented with fetal bovine serum 10% (Sigma Aldrich F7524), Penincillin/Streptamycin 1% (Sigma Aldrich P4333) and 500 mM IBMX, then distributed in 384-well microplates at a density of l.OxlO 4 cells/well (35 pL). Stock solutions of the compounds were prepared at a concentration of 1 mM in DMSO. Then, Compounds to be tested were diluted in assay buffer and a 35 pL aliquot transferred to the plate containing the cells to reach final assay concentrations of 1*10 14 - 1*10 7 M.
  • cell culture media Eagle's minimal essential medium IX + GlutaMAX (Gibco 31966-021)
  • fetal bovine serum 10% Sigma Aldrich F7524
  • Penincillin/Streptamycin 1% Sigma Ald
  • the standard reference agonist is GLP-l-G 2 -NFl2, which is tested in each experiment at several concentrations to generate a concentration-response curve from which its EC50 value and SEM is calculated using GraphPad Prism.
  • the EC50 data of Compound 77 is shown in Figure 16. Compound 77 demonstrated and EC50 of 0.08 pM with a SEM of 0.01 pM.
  • mice were housed in groups of 5-6 mice/cage under controlled temperature (22 ⁇ 2°C), humidity (50 ⁇ 10 %) and light cycle (12:12). Mice were housed in ventilated polycarbonate cages (IVC Mouse Green line GR500 from Tecniplast, France), enriched with nesting material (sizzle-nest from Bio Services so the mice in a cage can build a complete covered nest) throughout the experimental phase.
  • IVC Mouse Green line GR500 from Tecniplast, France
  • nesting material sizzle-nest from Bio Services so the mice in a cage can build a complete covered nest
  • ALT alanine transaminase
  • AST aspartate transaminase
  • BW body weight
  • the vehicle (PBS) and compound 77 (4 pg or 20 pg per mouse) were administered via i.p. route every week for 18 weeks.
  • the reference item obeticholic acid (OCA) was given in the diet (incorporated in the diet at 0.21mg/g).
  • Mice treated with OCA were also treated with vehicle i.p. every week to get similar experimental conditions in all groups.
  • At 18 weeks of treatment (25 weeks of diet) all mice were sacrificed after maximal blood collection and tissue collection.
  • mice were weighed and 6- hr fasted.
  • Whole blood 100 pL/EDTA was collected via tail nick for measurement of fasted blood glucose, plasma insulin, ALT and AST levels.
  • Plasmatic insulin levels were determined by an Elisa kit (Alpco), and blood glucose using a glucometer Accu-Check (Roche).
  • the ALT and AST levels were measured by the Anexplo facility of Rangueil Hospital (ABX Pentra 400, Horiba).
  • Liver TGs (PAP 150, Biomerieux), FFAs (Wako Chemicals) and cholesterol (RTU, Biomerieux) contents were determined from liver homogenate after lipid solubilization with deoxycholate, as described in Briand et al. (citation below) using commercial kits according to manufacturer's protocol.
  • Histology The histological preparation and analyses were performed by Histalim (Montpellier). Briefly, collected tissues were fixed with 4% paraformaldehyde in PBS for 48 hours and embedded in paraffin blocs. Five micron sections were stained with hematoxylin and eosin and Sirius Red. Images were acquired under light. The NAS score was performed by an independent pathologist to avoid any bias during the analysis. Histopathological NAFLD Activity scoring (NAS) and lobular fibrosis were performed using the established criteria: steatosis, lobular inflammation, fibrosis and hepatocellular ballooning. These four variables were qualitatively assessed and ranked with a score.
  • the sequence identifiers of the primers are indicated in Table 3.
  • Quantitative RT- PCR was performed in a Light Cycler PCR System (PikoReal Real-Time PCR System ThermoScientific) by using the SYBR Green qPCR Master Mix (Dynamo Flash Sybr green qPCR kit; ThermoFisher), according to the manufacturer's instructions.
  • the sequence identifies of the primers are shown in Table 6. Relative amounts of mRNA were determined using the AACt method for the quantification and were normalized to 18S RNA expression, for which Ct values remain unaltered by the treatments.
  • Compound 77 reduces liver disease markers in DIN mice.
  • an initial validation of the experimental model was performed.
  • C57BL6/J mice were fed a high fat/cholesterol diet with fructose in drinking water.
  • 6 weeks of diet inducing NASH (DIN) were sufficient to induce obesity with a higher glycaemia and HOMA-IR, but no difference detected with regards to liver transaminases (ALT and AST) when compared to control chow diet (Table 7).
  • Triglycerides (pg/mg) 21 ,3 ⁇ 3,1 126,5 ⁇ 15,9 *** 22,7 ⁇ 2,2 197,5 ⁇ 17,0 *** Fatty acids (nmol/mg) 15, 7 ⁇ 1 ,5 55,6 ⁇ 4,1 *** 13, 7 ⁇ 1 ,0 66,5 ⁇ 6,4 ***
  • Compound 77 limits the diet induced liver steatosis and fibrosis. After 18 weeks of treatment period, the mice were sacrificed to analyze the liver tissue composition. As shown in Figure 12A-12C, compound 77 tended to reduce the hepatic cholesterol, triglycerides and fatty acids in a dose dependent manner. The effects of OCA were more pronounced on hepatic cholesterol, but with similar efficiency to compound 77 at 20 pg dose regarding liver triglycerides (TGs) and fatty acids (FAs) lowering ( Figures 12A to 12C).
  • TGs liver triglycerides
  • FAs fatty acids
  • NAS-score NAFLD scoring system
  • NASH-related inflammation and fibrosis are limited by compound 77.
  • OCA oxygen deficiency gene
  • the expression of different markers were examined by RT-qPCR. It was observed that compound 77 tended to reduce the inflammatory markers monocyte chemoattractant protein-1 (MCP-1), Tumor necrosis factor a (TNF- a) and significantly reduced the macrophage marker F4/80 ( Figure 14A).
  • MCP-1 monocyte chemoattractant protein-1
  • TNF- a Tumor necrosis factor a
  • F4/80 Figure 14A
  • Compound 77 also reduced the expression of fibrotic markers collagen la 1 (Collal), a-smooth muscle actin (a-SMA) and transforming growth factor-b (TGF-b) at both doses (Figure 14B), confirming the significant effects observed at the histological level.
  • Compound 77 presents anti-diabetic properties in obese mice. GLP-1 and its analogues stimulate the insulin release by the b-cells of the pancreas leading to an efficient hypoglycemic effect.
  • blood glucose and insulin levels were followed during all the treatment period. It was observed that compound 77 has a dose dependent hypoglycemic effect that was significant at both doses at week 5 and maintained during all the treatment period (Figure 15A). Similar trends were observed for insulin levels that remained significantly lower from week 5 to the end of the treatment period ( Figure 15B).
  • NAFLD refers to liver disorders in which an excessive hepatic lipid content can progress to more severe disease including NASH and cirrhosis. This accumulation of lipids in the liver can be the consequence of a high rate of de novo hepatic lipogenesis; a high nutritional uptake or an important free fatty acid release from the adipose tissue.
  • the incretin hormone GLP-1 appeared as an interesting therapeutic strategy to prevent NAFLD. Indeed, GLP-1 and its analogues not only normalize blood glucose levels but also induce satiety, regulate gastrointestinal motor functions and decrease high fat diet-induced hepatic steatosis and inflammation.
  • GLP-1 analogues are already used clinically, such as exenatide, semaglutide, liraglutide or lixisenatide.
  • different strategies have been used including amino acid modifications, conjugation to lipids that promote binding to plasma albumin, and fusion to large proteins like albumin and Fc fragment of the IgGs. These modifications increased the molecules stability and reduced their administration frequency as well as their adverse effects.
  • the examples of the present disclosure confirm the protective effects of a newly designed GLP-1 analogue harboring an ureido monosubstitution on liver steatosis progression in mice.
  • the long-lasting effects of this molecule may be an interesting strategy to circumvent the adverse effects of repeated treatments in human.
  • the GLP-1 analogues have been shown to reduce hepatic steatosis in mouse models of NASH by reducing the expression of inflammatory markers, and/or the ER- stress markers, and/or the fatty acid load in hepatocytes. Excess in saturated fatty acid load may induce an ER-stress that activate stress signaling pathways leading to hepatocyte ballooning and finally to apoptosis.
  • Gene expression analysis in the examples of the present disclosure suggested that compound 77 prevents the NASH progression by limiting the expression of inflammation and fibrosis markers and reducing the hepatocyte lipid accumulation without affecting the ER-stress. Therefore, the reduction of the hepatocyte ballooning observed at the histological level is likely due primarily to a reduction of fatty acid loading rather than a dilation of the ER and disruption of its homeostasis.
  • the FXR-agonists upregulate Small Heterodimer Partner (SHP) in hepatic stellate cells and markedly reduce collagen I levels, abolishing MMP2 production and inhibiting the expression of tissue inhibitor of metalloproteinase 1 (TIMP1).
  • SHP Small Heterodimer Partner
  • This example also compares the properties of compound 77 to the FXR agonist OCA, the most advanced drug for NASH treatment.
  • the beneficial effects of OCA are mediated by the decreased expression of the master lipogenic regulator sterol-regulatory element binding protein (SREBP)-lc and the increase of the hepatic scavenger receptors expression (SRB1), which accelerates reverse cholesterol transport by increasing the clearance of HDL.
  • SREBP master lipogenic regulator sterol-regulatory element binding protein
  • SRB1 hepatic scavenger receptors expression
  • the present disclosure provides a method of treating, preventing, or ameliorating at least one symptom of a disease or disorder in a subject, the method comprising administering a composition comprising an effective amount of a chimeric compound or foldamer to a subject in need thereof, wherein the composition is effective for treating, preventing, or ameliorating at least one symptom of the disease or disorder and the chimeric compound or foldamer is a GLP-1 analogue having at least one (e.g., a plurality of) amino acid of the compound or foldamer substituted with a residue selected from an aminourea, an aminothiourea, and an aminoguanidine, wherein the disease or disorder is selected from the group consisting of diabetes, obesity, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), a neurodegenerative or cognitive disease or disorder, heart disease, microvascular disease, atherosclerosis or cardiovascular disease, myocardial infarction, strokes, or a
  • NAFLD non-alcoholic
  • the present disclosure provides a method of treating, preventing, or ameliorating at least one symptom of, a disease or disorder in a subject, the method comprising administering a composition comprising an effective amount of a chimeric compound or foldamer to a subject in need thereof, wherein the chimeric compound or foldamer is a GLP-1 analogue having at least one amino acid substituted with a residue having a urea, a thiourea, or a guanidine moiety resulting in an N, N'-linked urea, thiourea, or guanidine bridging unit, respectively, wherein the disease or disorder is selected from the group consisting of diabetes, obesity, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), a neurodegenerative or cognitive disease or disorder, heart disease, microvascular disease, atherosclerosis or cardiovascular disease, myocardial infarction, strokes, or a combination thereof, and wherein the
  • the GLP-1 analogue is selected from the group consisting of lixisenatide, exenatide, semaglutide, liraglutide, albiglutide, dulaglutide, derivatives thereof, and combinations thereof.
  • an amino acid of the chimeric compound or foldamer is an amino acid modified with a fatty acid glutamate (e.g., palmitoyl glutamate).
  • a fatty acid glutamate e.g., palmitoyl glutamate
  • the substituted amino acid is located in the first 4 amino acids (N-terminal) of the peptide.
  • the substituted amino acid is located at or within 3 amino acids of an amino acid that is key for the interaction between the protein and a receptor, ligand or other polypeptide that interacts with the peptide.
  • the substituted amino acid is located at or within 3 amino acids of an amino acid that is key for at least one pharmacokinetic property of the peptide.
  • the substituted amino acid is located at or within 3 amino acids of an amino acid that is key for at least one physical property of the peptide.
  • the substitution is an N,N' linked substitution.
  • the chimeric compound or foldamer includes the amino acid sequence of SEQ ID NO: 15.
  • the chimeric includes an amino acid modified with a fatty acid glutamate (e.g., palmitoyl glutamate).
  • a fatty acid glutamate e.g., palmitoyl glutamate
  • the chimeric compound or foldamer is compound 77.
  • the neurodegenerative or cognitive disease or disorder includes peripheral neuropathy, multiple system atrophy, chronic traumatic encephalopathy (CTE), spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), vascular dementia, dementia with Lewy bodies (DLB), frontotemporal dementia, Creutzfeldt-Jakob disease, idiopathic normal pressure hydrocephalus, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic sclerosis, multiple sclerosis, traumatic brain injury, spinal cord injury, or a combination thereof.
  • CTE chronic traumatic encephalopathy
  • SCA spinocerebellar ataxia
  • SMA spinal muscular atrophy
  • vascular dementia dementia with Lewy bodies
  • DLB dementia with Lewy bodies
  • Creutzfeldt-Jakob disease Creutzfeldt-Jakob disease
  • idiopathic normal pressure hydrocephalus Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic sclerosis, multiple
  • the composition further comprises a pharmaceutically acceptable carrier or excipient.
  • At least one amino acid side chain is modified with a fatty acid glutamic acid.
  • At least one amino acid side chain is modified with a palmitoyl glutamic acid
  • the method further comprises co administer an farnesoid X receptor (FXR) agonist.
  • FXR farnesoid X receptor
  • the FXR agonist is selected from cafestol, chenodeoxycholic acid, obeticholic acid, fexaramine, or a combination thereof.
  • the present disclosure provides a method of improving at least one biological property of a peptide or peptidomimetic, wherein the biological activity is selected from the group consisting of therapeutic effect, stability toward enzymatic degradation, stability, solubility, affinity for a receptor, ligand or other polypeptide or peptide that interacts with the native, natural or unmodified peptide, clearance, and combinations thereof, the method comprising: substituting a plurality of amino acids of the peptide or peptidomimetic with a residue selected from an aminourea, a thiourea, and a guanidine, wherein at least one non-consecutive amino acid has been monosubstituted by an aminourea, a thiourea, or a guanidine.
  • the monosubstituted amino acid is located in the first 4 amino acids (N-terminal) of the peptide.
  • the monosubstituted amino acid is located at or within 3 amino acids of an amino acid that is key for the interaction between the protein and a receptor, ligand or other polypeptide that interacts with the native, natural, or unmodified protein.
  • a mino acid is located at or within 3 amino acids of an amino acid that is key for at least one pharmacokinetic property of the peptide.
  • peptide is 6 or more amino acids.
  • substitution is an N,N' linked substitution.
  • residue of the urea, the thiourea, the guanidine are independently selected from the group consisting of:
  • X is independently selected from the group consisting of 0, S, NH;
  • R is independently selected from the group consisting of hydrogen, any side chain of a natural amino acid, linear, branched or cyclic Cl-C6-alkyl, alkenyl or alkynyl; mono- or -bicyclic aryl, mono or bicyclic heteroaryl having up to five heteroatoms selected from N, O and S; mono or bicyclic a ryl-Cl-C6-a Ikyl, alkenyl or alkynyl; Cl- C6-alkyloxy, aryloxy, heteroaryloxy, thio, Cl-C6-a Ikylthio, amino, mono ordi-Cl-C6- alkylamino, carboxylic acid, carboxamide mono- or di-Cl-C6-alkylcarboxamine, sulfonamide, urea, mono-di or tri-substituted urea, thiourea, guanidine;
  • R 1 is independently selected from the group consisting of hydrogen, linear,
  • R 2 is independently selected from the group consisting of hydrogen, linear, branched or cyclic Cl-C6-alkyl, alkenyl or alkynyl; mono- or -bicyclic aryl, mono or bicyclic heteroaryl having up to five heteroatoms selected from N, 0 and S;
  • aminourea, the thiourea, the guanidine are independently selected from the group consisting of:
  • X is independently selected from the group consisting of O, S, NH;
  • R is independently selected from the group consisting of hydrogen, any side chain of a natural amino acid, linear, branched or cyclic Cl-C6-alkyl, alkenyl or alkynyl; mono- or -bicyclic aryl, mono or bicyclic heteroaryl having up to five heteroatoms selected from N, O and S; mono or bicyclic a ryl-Cl-C6-a Ikyl, alkenyl or alkynyl; Cl- C6-alkyloxy, aryloxy, heteroaryloxy, thio, Cl-C6-a Ikylthio, amino, mono ordi-Cl-C6- alkylamino, carboxylic acid, carboxamide mono- or di-Cl-C6-alkylcarboxamine, sulfonamide, urea, mono-di or tri-substituted urea, thiourea, guanidine;
  • R 1 is independently selected from the group consisting of hydrogen, linear,
  • R 2 is independently selected from the group consisting of hydrogen, linear, branched or cyclic Cl-C6-alkyl, alkenyl or alkynyl; mono- or -bicyclic aryl, mono or bicyclic heteroaryl having up to five heteroatoms selected from N, 0 and S;
  • R 4 together with the carbon atoms to which it is attached independently defines a substituted or unsubstituted, monocyclic or bicyclic C3-C10 cycloalkyl, cycloalkenyl or heterocyclic ring having one or more N, 0,or S atom(s) as the heteroatom(s); and substitutents on the cycloalkyl, cycloalkenyl or heterocycle moieties are
  • peptide has an amino acid sequence selected from SEQ ID NOS: 1, 14, 16, 19 (potent duodecimal peptide inhibitor (PMI)), 66, 71, 75, or 76.
  • PMI potent duodecimal peptide inhibitor
  • the present disclosure provides a peptide-oligourea compound or foldamer produced according to the method of the present disclosure.
  • the peptide is a class B GPCR ligand or derivative thereof.
  • class B GPCR ligand or derivative thereof is selected from the group consisting of lixisenatide, exenatide, semaglutide, liraglutide, albiglutide, dulaglutide, derivatives thereof, and combinations thereof.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising the peptide-oligourea compound or foldamer according to the present disclosure and a pharmaceutically acceptable carrier or excipient.
  • the present disclosure provides a method of treating, preventing, or ameliorating at least one symptom of, a disease or disorder in a subject, the method comprising administering an effective amount of the peptide-oligourea compound or foldamer of the present disclosure or the pharmaceutical composition of claim 19 to a subject in need thereof, wherein the peptide or pharmaceutical composition is effective for treating, preventing, or ameliorating at least one symptom of the disease or disorder.
  • the disease or disorder is selected from the group consisting of diabetes (such as diabetes mellitus type 1 or diabetes mellitus type 2), a neurodegenerative disease or disorder (such as peripheral neuropathy, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic sclerosis, multiple sclerosis, traumatic brain injury, or spinal cord injury), or combinations thereof.
  • diabetes such as diabetes mellitus type 1 or diabetes mellitus type 2
  • a neurodegenerative disease or disorder such as peripheral neuropathy, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic sclerosis, multiple sclerosis, traumatic brain injury, or spinal cord injury
  • Glucagon-like peptide-1 receptor agonism improves metabolic, biochemical, and histopathological indices of nonalcoholic steatohepatitis in mice.
  • GLP-1 analogs reduce hepatocyte steatosis and improve survival by enhancing the unfolded protein response and promoting macroautophagy.

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Abstract

L'invention concerne des procédés d'administration de ces composés oligomères à des fins de traitement et de prévention d'une maladie chez un mammifère. En particulier, l'invention concerne des médicaments comprenant divers nouveaux composés oligomères et leurs sels pharmaceutiquement acceptables. Les composés de l'invention peuvent éventuellement être administrés avec un excipient pharmaceutiquement acceptable et/ou un principe pharmacologiquement actif supplémentaire, ou une combinaison de ceux-ci.
EP19791170.4A 2018-11-30 2019-10-03 Composés foldamères de peptide-oligourée et leurs procédés d'utilisation Withdrawn EP3886892A1 (fr)

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