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EP3707149A1 - Selenogalactosidverbindungen zur behandlung von systemischen insulinresistenzstörungen und deren verwendung - Google Patents

Selenogalactosidverbindungen zur behandlung von systemischen insulinresistenzstörungen und deren verwendung

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Publication number
EP3707149A1
EP3707149A1 EP18874558.2A EP18874558A EP3707149A1 EP 3707149 A1 EP3707149 A1 EP 3707149A1 EP 18874558 A EP18874558 A EP 18874558A EP 3707149 A1 EP3707149 A1 EP 3707149A1
Authority
EP
European Patent Office
Prior art keywords
group
substituted
heteroaryl
naphthyl
group substituted
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Withdrawn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
EP18874558.2A
Other languages
English (en)
French (fr)
Inventor
Peter G. Traber
Eliezer Zomer
Deirdre SLATE
Joseph M. Johnson
Ryan George
Sharon Shechter
Raphael NIR
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.)
Galectin Sciences LLC
Original Assignee
Galectin Sciences LLC
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Filing date
Publication date
Application filed by Galectin Sciences LLC filed Critical Galectin Sciences LLC
Publication of EP3707149A1 publication Critical patent/EP3707149A1/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/056—Triazole or tetrazole radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/80—Polymers containing hetero atoms not provided for in groups A61K31/755 - A61K31/795
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H5/00—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium
    • C07H5/08—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium to sulfur, selenium or tellurium

Definitions

  • aspects of the invention relate to compounds, compositions and methods of treating systemic insulin resistance associated with obesity where elevated galectin-3 interacts with insulin receptor.
  • treatment with compounds of this invention can restore sensitivity to insulin activity in various tissues.
  • the monogalactoside, digalactoside or oligosaccharides of galactose of the present invention are metabolically more stable than compounds having an O-glycosidic or S-glycosidic bond.
  • the compound is a compound having Formula (1 ) or Formula (2) or a pharmaceutically acceptable salt or solvate thereof:
  • W is selected from the group consisting of O, N, S, CH2, NH, and Se
  • Y is selected from the group consisting of O, S, C, NH, CH2, Se, S,
  • R 2 are independently selected from the group consisting of CO, 02, S02, SO, P02, PO, CH, Hydrogen, or combination of these and a) an alkyl group of at least 3 carbons, an alkenyl group of at least 3 carbons, an alkyl group of at least 3 carbons substituted with a carboxy group, an alkenyl group of at least 3 carbons substituted with a carboxy group, an alkyl group of at least 3 carbons substituted with an amino group, an alkenyl group of at least 3 carbons substituted with an amino group, an alkyl group of at least 3 carbons substituted with both an amino and a carboxy group, an alkenyl group of at least 3 carbons substituted with both an amino and a carboxy group, and an alkyl group substituted with one or more halogens, b) a phenyl group substituted with at least one car boxy group, a phenyl group substituted with at least one halogen, a phenyl group
  • the compound is a 3-derivatized diselenogalactoside bearing a fluorophenyl-triazole.
  • the compound is in a free form.
  • the free form is an anhydrate.
  • the free form is a solvate, such as a hydrate.
  • the compound is in a crystalline form.
  • Some aspects of the invention relates to methods of treating insulin resistance, the method comprising administering to a subject in need thereof a composition comprising a therapeutically effective amount of the compound of formulae (1 ), (2), (3), (4), (5), (6) or (7) or a pharmaceutically acceptable salt or solvate thereof.
  • the compound can be used in conjunction with an active agent.
  • the active agent is an immunomodulatory, an anti-inflammatory drug, a vitamin, a nutraceutical drug, a supplement, or combinations thereof.
  • administration of the compound of the present invention and the active agent produces a synergistic effect.
  • Some aspects of the invention relate to a method of treating diseases due to disruption in the activity of TGFpi (Transforming Growth Factor beta 1 ) by reversal of the Galectin-3 interaction with its receptor (TGFpi -Receptor) so as to recover normal regenerative activity in tissues.
  • TGFpi Transforming Growth Factor beta 1
  • TGFpi -Receptor receptor for TGFpi
  • Some aspects of the invention relate to a method of treating diseases associated with the Transforming Growth Factor Beta signaling pathway that involved many cellular and pathological processes in both the adult and embryo development including cell growth, cell differentiation, apoptosis, cellular homeostasis and other cellular functions.
  • Some aspects of the present invention relate to a compound of formula (1 ), (2), (3), (4), (5), (6) or (7) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating a disorder relating to the binding of a galectin in a subject in need thereof.
  • Some aspects of the present invention relate to a compound of formulae (1 ), (2), (3), (4), (5), (6) or (7) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating a disorder relating to the binding of galectin-3 to a ligand in a subject in need thereof.
  • Figure 1 depicts a high-definition 3D structure of Galectin-3 Carbohydrate Recognition Domain (CRD) binding pocket with 3 potential sites of interaction.
  • CCD Carbohydrate Recognition Domain
  • Figure 2 depicts the CRD pocket location in the Galectin-3 C-terminal with bound lactose unit.
  • Figure 3 depicts a map of the Galectin-3 CRD site vicinity - potential cooperative amino-acids for enhanced binding.
  • Figure 5B depicts a Fluorescence Resonance Energy Transfer analytical assay (FRET Format) for screening compounds that inhibit Galectin-3 interaction with its Glycoprotein-ligand (for example TGFbl -Receptor FRET format) according to some embodiments.
  • FRET Format Fluorescence Resonance Energy Transfer analytical assay
  • Figure 6B depicts a functional assay to screen compounds that inhibit the Galectin-3 interaction with its Glycoprotein-ligand (for example Insulin-Receptor ELISA format) according to some embodiments.
  • Glycoprotein-ligand for example Insulin-Receptor ELISA format
  • Figure 7 provides examples of Compounds IC50 by Fluorescent Polarization - CRD specific assay of compounds according to some embodiments.
  • the composition or the compound can be used in the treatment of heart disorders including heart failure, arrhythmias, and uremic cardiomyopathy.
  • the composition or the compound can be used in the treatment of kidney diseases including glomerulopathies and interstitial nephritis.
  • the composition or the compound can be used in the treatment of inflammatory, proliferative and fibrotic skin disorders including but not limited to psoriasis and scleroderma.
  • aspects of the invention relates to methods of treating inflammatory and fibrotic disorders in which galectins are at least in part involved in the pathogenesis, by enhancing anti-fibrosis activity in organs, including but not limited to liver, kidney, lung, and heart.
  • aspects of the invention relates to methods relates to a composition or a compound that has a therapeutic activity to treat nonalcoholic steatohepatitis (NASH).
  • the invention elates to a method to reduce the pathology and disease activity associated with nonalcoholic steatohepatitis (NASH).
  • aspects of the invention relates to a composition or a compound to treat neoplastic conditions (e.g. benign or malignant neoplastic diseases) in which galectins are at least in part involved in the pathogenesis by inhibiting processes promoted by the increase in galectins.
  • the invention relates a method of treating neoplastic conditions (e.g. benign or malignant neoplastic diseases) in which galectins are at least in part involved in the pathogenesis by inhibiting processes promoted by the increase in galectins.
  • the composition or a compound can be used to treat or prevent tumor cell growth, invasion, metastasis, and neovascularization.
  • the composition or a compound can be used to treat primary and secondary cancers.
  • Galectins also known as galaptins or S-lectins
  • S-lectins are a family of lectins which bind beta-galactoside.
  • Galectin as a general name was proposed in 1994 for a family of animal lectins (Barondes, S. H., et al.: Galectins: a family of animal beta- galactoside-binding lectins. Cell 76, 597-598, 1994).
  • the family is defined by having at least one characteristic carbohydrate recognition domain (CRD) with an affinity for beta-galactosides and sharing certain sequence elements.
  • CCD characteristic carbohydrate recognition domain
  • galectins into three subgroups including: (1 ) galectins having a single CRD, (2) galectins having two CRDs joined by a linker peptide, and (3) a group with one member (galectin-3) which has one CRD joined to a different type of N-terminal domain.
  • the galectin carbohydrate recognition domain is a beta- sandwich of about 135 amino acids. The two sheets are slightly bent with 6 strands forming the concave side, also called the S-face, and 5 strands forming the convex side, the F-face).
  • the concave side forms a groove in which carbohydrate is bound (Leffler H, Carlsson S, Hedlund M, Qian Y, Poirier F (2004). "Introduction to galectins”. Glycoconj. J. 19 (7-9): 433-40).
  • the carbohydrate domain binds to galactose residues associated with glycoproteins.
  • Galectins show an affinity for galactose residues attached to other organic compounds, such as in lactose [( -D-Galactosido)-D- glucose], N-acetyl-lactosamine, poly-N-acetyllactosamine, galactomannans, or fragments of pectins.
  • lactose ( -D-Galactosido)-D- glucose]
  • N-acetyl-lactosamine N-acetyl-lactosamine
  • poly-N-acetyllactosamine poly-N-acetyllactosamine
  • galactomannans or fragments of pectins.
  • At least fifteen mammalian galectin proteins have been identified which have one or two carbohydrate domains in tandem.
  • Galectin proteins are found in the intracellular space where they have been assigned a number of functions and they are also are secreted into the extracellular space where they have different functions. In the extracellular space, galectin proteins can have multiple functions that are mediated by their interaction with galactose containing glycoproteins including promoting interactions between glycoproteins that may modulate function or, in the case of integral membrane glycoprotein receptors, modification of cellular signaling (Sato et al "Galectins as danger signals in host-pathogen and host-tumor interactions: new members of the growing group of "Alarmins.” In “Galectins,” (Klyosov, et al eds.), John Wiley and Sons, 1 15-145, 2008, Liu et al "Galectins in acute and chronic inflammation," Ann.
  • Galectins have been shown to have domains which promote homodimerization. Thus, galectins are capable of acting as a "molecular glue" between glycoproteins. Galectins are found in multiple cellular compartments, including the nucleus and cytoplasm, and are secreted into the extracellular space where they interact with cell surface and extracellular matrix glycoproteins. The mechanism of molecular interactions can depend on the localization. While galectins can interact with glycoproteins in the extracellular space, the interactions of galectin with other proteins in the intracellular space generally occurs via protein domains. In the extracellular space the association of cell surface receptors may increase or decrease receptor signaling or the ability to interact with ligands.
  • Galectin proteins are markedly increased in a number of animal and human disease states, including but not limited to diseases associated with inflammation, fibrosis, autoimmunity, and neoplasia. Galectins have been directly implicated in the disease pathogenesis, as described below.
  • diseases states that may be dependent on galectins include, but are not limited to: systemic insulin resistance, acute and chronic inflammation, allergic disorders, asthma, dermatitis, autoimmune disease, inflammatory and degenerative arthritis, immune- mediated neurological disease, fibrosis of multiple organs (including but not limited to liver, lung, kidney, pancreas, and heart), inflammatory bowel disease, atherosclerosis, heart failure, ocular inflammatory disease, a large variety of cancers.
  • galectins are important regulatory molecules in modulating the response of immune cells to vaccination, exogenous pathogens and cancer cells.
  • Galectin proteins such as galectin-1 and galectin-3 have been shown to be markedly increased in inflammation, fibrotic disorders, and neoplasia (Ito et al. "Galectin-1 as a potent target for cancer therapy: role in the tumor microenvironment", Cancer Metastasis Rev. PMID: 22706847 (2012), Nangia- Makker et al.
  • 201 1 Lefranc et al., "Galectin-1 mediated biochemical controls of melanoma and glioma aggressive behavior," World J. Biol. Chem. 2: 193-201 , 201 1 , Forsman et al., "Galectin 3 aggravates joint inflammation and destruction in antigen-induced arthritis," Arthritis Reum. 63: 445-454, 201 1 , de Boer et al., "Galectin-3 in cardiac remodeling and heart failure," Curr. Heart Fail. Rep. 7, 1 -8, 2010, Ueland et al.
  • Galectin-3 testing may be useful in helping physicians determine which patients are at higher risk of hospitalization or death.
  • the BGM Galectin-3® Test is an in vitro diagnostic device that quantitatively measures Galectin-3 in serum or plasma and can be used in conjunction with clinical evaluation as an aid in assessing the prognosis of patients diagnosed with chronic heart failure. Measure of the concentration of endogenous protein Galectin-3 can be used to predict or monitor disease progression or therapeutic efficacy in patients treated with cardiac resynchronization therapy (see US 8,672,857).
  • Galectin-3 has been shown to be elevated in patients with metabolic disorders and in obesity population with diabetes associated with systemic insulin resistance. High levels of serum Galectin-3 have been shown to be associated with obesity and diabetes. Diabetes is an enduring disease which can be resolved but can be prevented by taking care. It is one of the commonly found metabolic syndromes in the world. Diabetes mellitus mainly associates with central nervous system and peripheral nervous system which are chronic complications. Diabetes mellitus is a commonly seen metabolic syndrome of diabetes where the body cannot use glucose and stores in blood which may damage kidneys, nerves, heart, eyes, and other complications.
  • Insulin resistance is a characteristic feature of patients with complications due to diabetes mellitus (T2DM) and is one of the defining clinical features in the Metabolic Syndrome (MetS).
  • MetS is an array of biochemical and metabolic diseases that estimate to effect over 20 % of adults (>20 years old) in the United States or approximately 50 million Americans. As the epidemic of obesity shows no signs of reversing, this number is likely to rise dramatically in the future.
  • Insulin resistance the key feature of type 2 diabetes could develop in someone with type 1 diabetes designate clinically as Double diabetes. Someone with double diabetes will always have type 1 diabetes present but with complication of insulin resistance. The most common reason for developing insulin resistance is obesity and whilst type 1 diabetes is not itself brought on by obesity.
  • Insulin is a hormone which has diverse functions including stimulation of nutrient transport into cells, regulation of variety of enzymatic activity and regulation of energy homeostasis. These functions involve glucose metabolism through intracellular signaling pathways in the liver, adipose tissue and muscles. In the liver, insulin resistance leads to elevated hepatic glucose production. In adipose tissue insulin resistance affecting lipase activity leading to anti-lipolytic effecting free fatty acid efflux out of adipocytes and increasing circulating free fatty acids.
  • Galectin-3 known to be mainly secreted by macrophages, may play a crucial role in this inflammation process thus it links inflammation to decrease in insulin sensitivity.
  • the insulin receptor is a transmembrane protein that is activated by bound insulin, IGF-I, IGF-II and belongs to the class of tyrosine kinase receptors. Insulin receptor plays a key role in the regulation of glucose homeostasis, that when dysfunction or metabolic impairment may result in a range of clinical manifestations including but not limited to diabetes.
  • the insulin receptor is encoded by a single gene I NSR, which during transcription may result in either IR-A or IR-B isoforms. Post-translational these isoform result in the formation of a proteolytically cleaved a and ⁇ subunits, which combine to form the final active -320 kDa transmembrane insulin receptor.
  • Insulin receptor and insulin interaction is checkpoint for a second pathway, the Ras-mitogen-activated protein kinase (MAPK) which mediates gene expression, and also affects the PI3K-AKT pathway that controls cell growth and differentiation.
  • Insulin receptor substrate is the common intermediate, which include four distinct family members, IRS1 -4. Defects in insulin signaling typically involve insulin receptor substrate- 1 (IRS1 ). Activation of the insulin receptor increase tyrosine phosphorylation of IRS1 which initiates signal transduction. However, when serine 307 is phosphorylated, signaling is diminished.
  • Additional inflammation- related negative regulators of IR or IRS1 including the suppressor of cytokine signaling (Socs) may promote ubiquitylation, where ubiquitin, a small protein, is attached to another targeted protein changing their functionality and subsequent degradation, e.g. IRS inactivation.
  • Some aspects of the invention relate to compounds and use of compounds that inhibit Galectin-3 to treat insulin resistance.
  • aspects of the invention relates to novel compounds that mimic the natural ligand of galectin proteins.
  • the compound mimics the natural ligand of galectin-3.
  • the compound mimics the natural ligand of galectin-1 .
  • the compound mimics the natural ligand of galectin-8.
  • the compound mimics the natural ligand of galectin-9.
  • the compound has a mono, di or oligomer structure composed of Galactose-Se core bound to the anomeric carbon on the galactose and which serves as a linker to the rest of the molecule.
  • the Galactose-Se core may be bound to other saccharide/amino acid/acids/group that bind galectin CRD (as shown in FIG. 1 in the high definition 3D structure of galectin-3) and together can enhance the compound's affinity to the CRD.
  • the Galactose-Se core may be bound to other saccharide/amino acid/acids/group that bind in "site B" of the galectin CRD (as shown in FIG. 1 in the high definition 3D structure of galectin-3) and together can enhance the compound's affinity to the CRD.
  • the compounds can have substitutions that interact with site A and/or site C to further improve the association with the CRD and enhance their potential as a therapeutic targeted to ga!ectin-dependent pathology.
  • the substituents can be selected through in-silico analysis (computer assisted molecular modeling) as described herein.
  • the substituents can be further screened using binding assay with the galectin protein of interest.
  • the compounds can be screened using a galectin-3 binding assay and/or an in-vitro inflammatory and fibrotic model of activated cultured macrophages (see Chavez-Ga!an, L. et a!. , Immunol. 2015; 8: 263).
  • the compounds comprise one or more specific substitutions of the core Ga!actose-Se.
  • the core Galactose-Se can be substituted with specific substituents that interact with residues located within the CRD. Such substituents can dramatically increase the association and potential potency of the compound as well as the 'drugability' characteristic.
  • Selenium has five possible oxidation states (-2, 0, +2, +4 and +6), and therefore is well represented in a variety of compounds with diverse chemical properties. Furthermore, selenium can be present in the place of sulphur in virtually all sulphur compounds, inorganic as well as organic.
  • selenium compounds organic and inorganic, are readily absorbed from the diet and transported to the liver - the prime organ for selenium metabolism.
  • the general metabolism of selenium compounds follows three major routes depending on the chemical properties, that is, redox-active selenium compounds, precursors of methylselenol and seleno-amino acids.
  • Selenium is generally known as an antioxidant due to its presence in selenoproteins as selenocysteine, but can also toxic. The toxic effects of selenium are, however, strictly concentration and chemical species dependent. One class of selenium compounds is a potent inhibitor of cell growth with remarkable tumor specificity (Misra, 2015). Sodium Selenite has been studied as a cytotoxic agent in Advanced Carcinoma (SECAR, see Brodin, Ola et al., 2015).
  • aspects of the invention relates to compounds comprising pyranosyl and/or furanosyl structures bound to a selenium atom on the anomeric carbon of the pyranosyl and/or furanosyl.
  • specific aromatic substitutions can be added to the galactose core or heteroglycoside core to further enhance the affinity of the selenium bound pyranosyl and/or furanosyl structures.
  • aromatic substitutions can enhance the interaction of the compound with amino acid residues (e.g. Arginine, Tryptophan, Histidine, Glutamic acid etc..) composing the carbohydrate- recognition-domains (CRD) of the lectins and thus strengthen the association and binding specificity.
  • the compound comprises monosaccharides, disaccharides and oligosaccharides of galactose or a heteroglycoside core bound to a selenium atom on the anomeric carbon of the galactose or of the heteroglycoside.
  • the compound is a symmetric digalactoside wherein the two galactosides are bound by one or more selenium bonds. In some embodiments, the compound is a symmetric digalactoside wherein the two galactosides are bound by one or more selenium bonds and wherein the selenium is bound to the anomeric carbon of the galactose. In some embodiments, the compound is a symmetric digalactoside wherein the two galactosides are bound by one or more selenium bonds and one or more sulfur bonds and wherein the selenium is bound to the anomeric carbon of the galactose. Yet in other embodiments, the compound can be an asymmetric digalactoside. For example, the compound can have different aromatic or aliphatic substitutions on the galactose core.
  • the compound is a symmetric galactoside wherein a single galactoside having one or more selenium on the anomeric carbon of the galactose.
  • the galactoside has one or more selenium bound to the anomeric carbon of the galactose and one or more sulfur bound to the selenium.
  • the compound can have different aromatic or aliphatic substitutions on the galactose core.
  • the compounds containing the Se containing molecules render the compound metabolically stable while maintaining the chemical, physical and allosteric characteristics for specific interaction with lectins or galectins known to recognize carbohydrates.
  • the digalactoside or oligosaccharides of galactose of the present invention are metabolically more stable than compounds having an O-glycosidic bond.
  • the digalactoside or oligosaccharides of galactose of the present invention are metabolically more stable than compounds having an S-glycosidic bond.
  • aspects of the invention relate to compounds based on galactoside structure with a Selenium bridge [X] to another galactose, hydroxyl cyclohexane, aromatic moiety, alkyl, aryl, amine, or amide.
  • alkyl group is meant to comprise from 1 to 12 carbon atoms, for example 1 to 7 or 1 to 4 carbon atoms or 3 to 7 carbon atoms.
  • the alkyl group may be straight- or branched-chain.
  • the alkyl group may also form a cycle comprising from 3 to 7 carbon atoms, preferably 3, 4, 5, 6, or 7 carbon atoms.
  • alkyl encompasses any of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, isopentyl, 3- methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 2,2-dimethylbutyl, 2,3- dimethylbutyl, n-heptyl, 2-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and 1 - methylcyclopropyl.
  • alkenyl group is meant to comprise from 2 to 12, for example 2 to 7 carbon atoms or 3 to 7 carbon atoms.
  • the alkenyl group comprises at least one double bond.
  • the alkenyl group encompasses any of vinyl, ally!, but-1 -enyi, but-2-enyl, 2,2-dimethylethenyl, 2,2- dimethy!prop-1 -enyi, pent-1 -enyl, pent-2-enyl, 2,3-dimethylbut-l -enyl, hex-1 -enyl, hex-2-enyl, hex-3-enyi, prop-1 ,2-dienyI, 4 ⁇ methylhex-1 -enyl, cyc!oprop-1 -eny!
  • alkoxy group relates to an alkoxy group containing 1 -12 carbon atoms, which may include one or more unsaturated carbon atoms. In some embodiments the alkoxy group contains 1 to 7 or 1 to 4 carbon atoms, which may include one or more unsaturated carbon atoms.
  • alkoxy group encompasses a methoxy group, an ethoxy group, a propoxy group, a isopropoxy group, a n-butoxy group, a sec-butoxy group, tert-butoxy group, pentoxy group, isopentoxy group, 3-methylbutoxy group, 2,2-dimethylpropoxy group, n- hexoxy group, 2-methylpentoxy group, 2,2-dimethylbutoxy group 2,3-dimethylbutoxy group, n-heptoxy group, 2-methylhexoxy group, 2,2-dimethylpentoxy group, 2,3- dimethylpentoxy group, cyclopropoxy group, cyclobutoxy group, cyclopentyloxy group, cyclohexyloxy group, cycloheptyloxy group, and 1 -methylcyclopropyloxy group.
  • aryl group is meant to comprise from 3 to 12 carbon atoms.
  • Said aryl group may be a phenyl group or a naphthyl group.
  • the above-mentioned groups may naturally be substituted with any other known substituents within the art of organic chemistry.
  • the groups may also be substituted with two or more of the said substituents. Examples of substituents are halogen, alkyl, alkenyl, alkoxy, nitro, sulfo, amino, hydroxy, and carbonyl groups. Halogen substituents can be bromo, fluoro, iodo, and chloro.
  • Alkyl groups are as defined above containing 1 to 7 carbon atoms.
  • Alkenyl are as defined above containing 2 to 7 carbon atoms, preferably 2 to 4.
  • Alkoxy is as defined below containing 1 to 7 carbon atoms, preferably 1 to 4 carbon atoms, which may contain an unsaturated carbon atom. Combinations of substituents can be present such as trifluoromethyl.
  • heteroaryl group is meant to comprise any aryl group comprising from 4 to 18 carbon atoms, wherein at least one atom of the ring is a heteroatom, i.e. not a carbon.
  • the heteroaryl group may be a pyridine, or an indole group.
  • the above-mentioned groups may be substituted with any other known substituents within the art of organic chemistry.
  • the groups may also be substituted with two or more of the substituents.
  • substituents are halogen, alkoxy, nitro, sulfo, amino, hydroxy, and carbonyl groups.
  • Halogen substituents can be bromo, fluoro, iodo, and chloro.
  • Alkyl groups are as defined above containing 1 to 7 carbon atoms.
  • Alkenyl are as defined above containing 2 to 7 carbon atoms, for example 2 to 4.
  • Alkoxy is as defined below containing 1 to 7 carbon atoms, for example 1 to 4 carbon atoms, which may contain an unsaturated carbon atom.
  • the compound is a monomeric-selenium polyhydroxylated- cycloalkanes compound having Formula (1 ) or Formula (2) or a pharmaceutically acceptable salt or solvate thereof:
  • W is selected from the group consisting of O, N, S, CH2, NH, and Se
  • Y is selected from the group consisting of O, S, NH, CH2, Se, S, S02, P02, amino acid, an hydrophobic linear and cyclic hydrophobic hydrocarbons derivatives including heterocyclic substitutions of molecular weight of about 50-200 D and combinations thereof,
  • Z is selected from the group consisting of O, S, N, CH, Se, S, P, and hydrophobic hydrocarbons derivatives including heterocyclic substitutions of 3 or more atoms,
  • F , R 2 , and R 3 are independently selected from the group consisting of CO, 02, S02, P02, PO, CH, Hydrogen, or combination of these and a) an alkyl group of at least 3 carbons, an alkenyl group of at least 3 carbons, an alkyl group of at least 3 carbons substituted with a carboxy group, an alkenyl group of at least 3 carbons substituted with a carboxy group, an alkyl group of at least 3 carbons substituted with an amino group, an alkenyl group of at least 3 carbons substituted with an amino group, an alkyl group of at least 3 carbons substituted with both an amino and a carboxy group, an alkenyl group of at least 3 carbons substituted with both an amino and a carboxy group, and an alkyl group substituted with one or more halogens, b) a phenyl group substituted with at least one carboxy group, a phenyl group substituted with at least one halogen, a
  • the compound is a dimeric-polyhydroxylated- cycloalkane compound. In some embodiment, the compound is an oligomeric selenium polyhydroxylated - cycloalkane compound with 3 or more units.
  • the compound has the general formulas (3) and (4) below or a pharmaceutically acceptable salt or solvate thereof:
  • W is selected from the group consisting of O, N, S, CH2, NH, and Se
  • Y is selected from the group consisting of O, S, C, NH, CH2, Se, S, P, amino acid, an hydrophobic linear and cyclic hydrophobic hydrocarbons derivatives including heterocyclic substitutions of molecular weight of about 50-200 D and combinations thereof,
  • Z is selected from the group consisting of O, S, N, CH, Se, S, S02, P02, and hydrophobic hydrocarbons derivatives including heterocyclic substitutions of 3 or more atoms,
  • P ⁇ and R 2 are independently selected from the group consisting of CO, 02, S02, SO, P02, PO, CH, Hydrogen, or combination of these and a) an alkyl group of at least 3 carbons, an alkenyl group of at least 3 carbons, an alkyl group of at least 3 carbons substituted with a carboxy group, an alkenyl group of at least 3 carbons substituted with a carboxy group, an alkyl group of at least 3 carbons substituted with an amino group, an alkenyl group of at least 3 carbons substituted with an amino group, an alkyl group of at least 3 carbons substituted with both an amino and a carboxy group, an alkenyl group of at least 3 carbons substituted with both an amino and a carboxy group, and an alkyl group substituted with one or more halogens, b) a phenyl group substituted with at least one car boxy group, a phenyl group substituted with at least one halogen, a phenyl
  • alkyl group relates to an alkyl group containing 1 -7 carbon atoms, which may include one or more unsaturated carbon atoms.
  • the alkyl group contains 1 -4 carbon atoms, which may include one or more unsaturated carbon atoms.
  • the carbon atoms in the alkyl group may form a straight or branched chain.
  • the carbon atoms in said alkyl group may also form a cycle containing 3, 4, 5, 6, or 7 carbon atoms.
  • alkyl group used herein encompasses methyl, ethyl, n-propyl, isopropyl, n-butyl, sec- butyl, tert-butyl, pentyl, isopentyl, 3-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2- methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 2,2- dimethylpentyl, 2,3-dimethylpentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and 1 -methylcyclopropyl.
  • the compound is a 3-derivatized diselenogalactoside bearing a fluorophenyl-triazole.
  • the compound has the general formulas (5) and (6) below or a pharmaceutically acceptable salt or solvate thereof:
  • X is Se, Se-Se, Se-S; S-Se, Se-S02, or S02-Se,
  • W is selected from the group consisting of O, N, S, CH2, NH, and Se
  • Y is selected from the group consisting of O, S, C, NH, CH2, Se, P, amino acid, an hydrophobic linear and cyclic hydrophobic hydrocarbons derivatives including heterocyclic substitutions of molecular weight of about 50-200 D and combinations thereof
  • Z is selected from the group consisting of O, S, N, CH, Se, S, P, and hydrophobic hydrocarbons derivatives including heterocyclic substitutions of 3 or more atoms
  • P , R 2 , R3 and R 4 are independently selected from the group consisting of CO, 02, S02, SO, P02, PO, CH, Hydrogen, or combination of these and a) an alkyl group of at least 3 carbons, an alkenyl group of at least 3 carbons, an alkyl group of at least 3 carbons substituted with a carboxy group, an alkenyl group of at least 3 carbons substituted with a carboxy group, an alkyl group of at least 3 carbons substituted with an amino group, an alkenyl group of at least 3 carbons substituted with an amino group, an alkyl group of at least 3 carbons substituted with both an amino and a carboxy group, an alkenyl group of at least 3 carbons substituted with both an amino and a carboxy group, and an alkyl group substituted with one or more halogens, b) a phenyl group substituted with at least one carboxy group, a phenyl group substituted with at least one halogen
  • the halogen is a fluoro, a chloro, a bromo or an iodo group.
  • the compound has the following formulas as shown in Table 1 and is an inhibitor of galectin-3.
  • Table 1 shows non-limiting examples of monomeric Se Galactosides.
  • the compound has the following formulas as shown in Table 2 and is an inhibitor of gaiectin-3.
  • Table 2 shows non-limiting examples of Di-Se saccharides.
  • the compound has the following formulas shown in Table 3 and is an inhibitor of gaiectin-3,
  • Table 3 shows non-limiting examples of oligo-Se saccharides.
  • Tetrameric Se-gaiactosides are expected to have higher affinity to the CRD versus the trimeric structure due to additional potential interaction of hydroxy! groups with amino-acids in the CRD vicinity (see Example 14).
  • the galactose-selenium compounds described herein have an enhanced stability as its structure is less prone to hydrolysis (metabolism) and oxidation, e.g. aromatic ring without substitutions, Carbon-Oxygen systems, Carbone-Nitrogen system etc.
  • Standard assays to evaluate the binding ability of the ligand toward target molecules are known in the art, including for example, ELISAs, western blots and RLAs. Suitable assays are described in detail herein.
  • the binding kinetics e.g., binding affinity
  • Biacore analysis Assays to evaluate the effects of the compounds on functional properties of the galecfin are described in further detail herein.
  • One way to determine protein-ligand binding affinity uses a structure- based model that can predict the interaction of the protein -ligand complex that results when the ligand binds to the protein. Such structures may be studied by x-ray crystallography. In some embodiments, compounds of interest can be screened "in silico" to predict the ligand's affinity to the lectin or galectin proteins using any scoring system known in the art.
  • a computational modeling can be used to facilitate structure-based drug design.
  • the in-silico model also enables to visually inspect the protein-compound interaction, conformational strain and possible steric clashes and avoid them.
  • the protein-ligand affinity can be scored using a Glide (Schrodinger, Portland OR).
  • GlideScore is a quantitative measurement that provides an estimate for a ligand binding free energy. It has many terms, including force field (electrostatic, van der Waals, etc ..
  • thermodynamic rationale for enthalpy-entropy compensation is based on the fact that, as the binding becomes stronger, enthalpy becomes more negative and entropy concomitantly tends to decrease due the formation of a tight complex. As such, ligands having the lowest GlideScore can be selected.
  • the GiideScore data showed that the introduction of Se to the anomeric carbon (G-625) on the galactose scores the same as the thiogalactoside (TD-139, also referred as G-240).
  • the results also showed that the thiogalactoside (TD-139) and the selenogalactoside compound (G-625) have comparable overall estimated predictor of free energy.
  • the thiogalactoside (TD-139) and the selenogalactoside compound (G-625) are expected to have comparable affinity to galectin-3 and inhibitor effects.
  • the Se atom allows the rest of the molecule (for example G-625) to fulfill the interactions seen with TD-139, but with a superior affinity to Galectin-3 vs. TD-139 as was shown in the Elisa based assay and fluorescent polarization assay.
  • the selenogalactoside of Formula (1 ) has an affinity to galectin-3 that is at least twice or at least three time stronger than TD-139.
  • the selenogalactosides of the present invention have an affinity to galectin-3 that is at least twice or at least three times stronger than the corresponding thiogalactoside.
  • the 'drugability' characteristic as defined by the computational structure analysis considers compounds: (1 ) stereoisomerization, (2) position of the hydroxyl groups on the sugar (e.g. axial or equatorial) and (3) position and nature of substituents.
  • Hydroxyl groups The position of the hydroxyl groups on the sugar (e.g. axial or equatorial) play an important role in compounds binding.
  • the present invention relates to compounds that are galactose-based bound to a Selenium atom bound to the anomeric carbon, serving as a linker to the rest of the molecule.
  • the compounds can have substituents capable of, or designed to, reach amino acids that are part of the binding site which were known and unknown to play a role in ligand's binding.
  • substituents capable of, or designed to, reach amino acids that are part of the binding site which were known and unknown to play a role in ligand's binding.
  • galectins bind the monosaccharide galactose with dissociation constants in the millimolar range. It has been shown that addition of N-acetyl glucosamine to galactose can provide additional interaction with neighboring sites boosts the compound affinity to galectin-3 over 10 fold (Bachhawat-Sikder Et al. FEBS Lett. 2001 Jun 29;500(1 -2):75-9).
  • Human Galectin-3 cavity is shallow with high solvent accessibility. It is very hydrophilic but capable of forming cation- ⁇ interactions with Arg144 and possibly Trp181 (Magnani 2009, Logan 201 1 ). It has been shown that upon ligand's binding, Arg144 moves 3.5A upwards from the protein surface to make a pocket for the Arene-Arginine interaction. It should be noted that Arg144 is absent in other galectin, e.g. Gal-1 , Gal-9 and this is being exploited in our in-silico model. Similarly, potency can be improved by exploiting cation- ⁇ interactions with the surface residue of Arg186. For example, triazole substitution at C3 of galactose has been reported to increase Galectin 3 affinity (Salameh BA et al. Bioorg. Med. Chem. Lett. 2005 Jul 15; 15(14):3344-6.)
  • Tryptophan 181 at subsite C is conserved throughout the galectin family.
  • a ⁇ - ⁇ stacking interaction between the Trp181 (W181 ) side chain and a carbohydrate residue (galactose being the natural carbohydrate occupant) accommodated within subsite C occurs in all reported galectin-saccharide complexes.
  • the side chain of Arg144 is capable of adopting different conformations due to its inherent flexibility that could contribute to greater affinity via an arginine-arene interaction (a cation- ⁇ ⁇ ⁇ - ⁇ stacking interaction) with the aromatic moiety.
  • galectin's key residues that affect ligand affinity were identified using computational alanine scanning mutagenesis (ASM) or an "in— silico-alanine-scan".
  • ASM computational alanine scanning mutagenesis
  • ASM can be performed by sequential replacement of individual residues by alanine to identify residues involved in protein function, stability and shape. Each alanine substitution examines the contribution of an individual amino acid to the functionality of the protein,
  • Galectin-3 R186S abolishes carbohydrate interactions.
  • the R186S was shown to have has a selectively lost affinity for LacNAc, a disaccharide moiety commonly found on glycoprotein glycans, and has lost the ability to activate neutrophil leukocytes and intracellular targeting into vesicles, (see Salomonsson E. et al., J Biol Chem. 2010 Nov 5;285(45):35079- 91 .)
  • Table 5 shows the in-silico Alanine scan comparison results using TD- 139 Compound
  • Table 6 shows the in-silico Alanine scan comparison results using 625 Compound having Formula 1
  • ** dG>100 suggests increase in ligand binding upon mutation to Alanine while dG ⁇ 100 suggests decrease in ligand binding upon mutation.
  • residue N174 play an important role in the binding of both TD-139 and G-625 compounds. Without being bound to the theory it is possible that residue N174 may help in positioning the Galactose core in 'the optimal orientation' that will enable the CRD site to recognize carbohydrate like framework of the oxygens.
  • the compounds of this invention may be prepared by the following general methods and procedures. It should be appreciated that where typical or preferred process conditions (e.g. reaction temperatures, times, molar ratios of reactants, solvents, pressures, pH etc.) are given, other process conditions may also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants, solvents used and pH etc. , but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • process conditions e.g. reaction temperatures, times, molar ratios of reactants, solvents, pressures, pH etc.
  • the compound was synthetized using the synthetic route shown in FIG. 4
  • compound G-625 was prepared as detailed in Example 10.
  • aspects of the invention relate to the use of the compounds described herein for the manufacture of medicaments. Some embodiments relate to the compounds or the use of the compounds having formulae (1 ), (2), (3), (4), (5), (6) or (7) or a pharmaceutically acceptable salt or solvate thereof. Some embodiments relate to the compounds or the use of the compounds of Tables 1 -4.
  • compositions comprising one or more of the compounds described herein.
  • the pharmaceutical compositions comprise one or more of the following: pharmaceutically acceptable adjuvant, diluent, excipient, and carrier.
  • pharmaceutically acceptable carrier refers to a carrier or adjuvant that may be administered to a subject (e.g., a patient), together with a compound of this invention, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount or an effective mount of the compound.
  • “Pharmaceutically acceptable carrier” refers to any and all solvents, dispersion media. The use of such media and compounds for pharmaceutically active substances is well known in the art.
  • the carrier is suitable for oral, intravenous, intramuscular, subcutaneous, parenteral, spinal or epidural administration (e.g., by injection or infusion).
  • the active compound can be coated in a material to protect the compound from the action of acids and other natural conditions that can inactivate the compound.
  • compositions comprising the compound of the invention and optionally a pharmaceutically acceptable additive, such as carrier or excipient.
  • the pharmaceutical composition comprising the compound of formulae (1 ), (2), (3), (4), (5), (6) or (7) or a pharmaceutically acceptable salt or solvate thereof and optionally a pharmaceutically acceptable additive, such as carrier or excipient.
  • the pharmaceutical composition comprising the compound of Tables 1 -4 or a pharmaceutically acceptable salt or solvate thereof and optionally a pharmaceutically acceptable additive, such as carrier or excipient.
  • the pharmaceutical composition comprises a compound described herein as active ingredient together with a pharmaceutically acceptable adjuvant, diluent, excipient or carrier.
  • a pharmaceutical composition can comprise from 1 to 99 weight % of a pharmaceutically acceptable adjuvant, diluent, excipient or carrier and from 1 to 99 weight % of a compound described herein.
  • the adjuvants, diluents, excipients and/or carriers that may be used in the composition of the invention are pharmaceutically acceptable, i.e. are compatible with the compounds and the other ingredients of the pharmaceutical composition, and not deleterious to the recipient thereof.
  • the adjuvants, diluents, excipients and carriers that may be used in the pharmaceutical composition of the invention are well known to a person within the art.
  • An effective oral dose of the compound of the present invention to an experimental animal or human may be formulated with a variety of excipients and additives that enhance the absorption of the compound via the stomach and small intestine.
  • the pharmaceutical composition of the present invention may comprise two or more compounds of the present invention.
  • the composition may also be used together with other medicaments within the art for the treatment of related disorders.
  • the pharmaceutical composition comprising one or more compounds described herein may be adapted for oral, intravenous, topical, intraperitoneal, nasal, buccal, sublingual, or subcutaneous administration, or for administration via the respiratory tract in the form of, for example, an aerosol or an air-suspended fine powder, or, for administration via the eye, intra-oculariy, intravitreally or comeally.
  • the pharmaceutical composition comprising one or more compounds described herein may be in the form of, for example, tablets, capsules, powders, solutions for injection, solutions for spraying, ointments, transdermal patches or suppositories, [00175]
  • Some aspects of the present invention relate to pharmaceutical composition comprising the compound described herein or a pharmaceutically acceptable salt or solvate thereof and optionally a pharmaceutically acceptable additive, such as carrier or excipient.
  • An effective oral dose could be 10 times and up to 100 times the amount of the effective parental dose.
  • An effective oral dose may be given daily, in one or divided doses or twice, three times weekly, or monthly.
  • the compounds described herein can be coadministered with one or more other therapeutic agents.
  • the additional agents may be administered separately, as part of a multiple dose regimen, from the compounds of this invention (e.g., sequentially, e.g., on different overlapping schedules with the administration of the compound of the invention.
  • these agents may be part of a single dosage form, mixed together with the compounds of this invention in a single composition.
  • these agents can be given as a separate dose that is administered at about the same time that the compound of the invention.
  • compositions include a combination of the compound of this invention and one or more additional therapeutic or prophylactic agents
  • both the compound and the additional agent can be present at dosage levels of between about 1 to 100%, and more preferably between about 5 to 95% of the dosage normally administered in a monotherapy regimen.
  • a therapeutically effective amount of the compound or of the composition can be compatible and effective in combination with a therapeutically effective amount of various anti-inflammatory drugs, vitamins, other pharmaceuticals and nutraceuticals drugs or supplement, or combinations thereof without limitation.
  • the compound of formula (1 ), (2), (3), (4), (5), (6) or (7) or of Tables 1 -4 or a pharmaceutically acceptable salt or solvate thereof is administered with a pharmaceutically acceptable adjuvant, excipient, formulation carrier or combinations thereof.
  • the compound of formula (1 ), (2), (3), (4), (5), (6) or (7) or of Tables 1 -4 or a pharmaceutically acceptable salt or solvate thereof is administered with an active agent and a pharmaceutically acceptable adjuvant, excipient, formulation carrier or combinations thereof.
  • the compound of formula (1 ), (2), (3), (4), (5), (6) or (7) or of Tables 1 - 4 or a pharmaceutically acceptable salt or solvate thereof is administered with one or more anti diabetic drug.
  • administration of the compound of the present invention and the active agent produces a synergistic effect.
  • the active agent is an antidiabetic drug.
  • the term "synergistic effect” refers to the correlated action of two or more agents of the present invention so that the combined action is greater than the sum of each acting separately.
  • the compounds of the present invention and the active agent can be administered simultaneously or sequentially.
  • aspects of the invention relates to a composition or a compound to treat neoplastic conditions in combination with other anti-neoplastic drugs including but not limited to checkpoint inhibitors (anti-CTLA2, anti-PD1 , anti-PDL1 ), other immune modifiers including but not limited to anti-OX40, and multiple other antineoplastic agents of multiple mechanisms.
  • anti-CTLA2, anti-PD1 , anti-PDL1 checkpoint inhibitors
  • other immune modifiers including but not limited to anti-OX40, and multiple other antineoplastic agents of multiple mechanisms.
  • aspects of the invention relates to a composition or a compound to treat neoplastic conditions in combination with other anti-neoplastic drugs including but not limited to checkpoint inhibitors (anti-CTLA2, anti-PD1 , anti-PDL1 ), other immune modifiers including but not limited to anti-OX40, and multiple other antineoplastic agents of multiple mechanisms.
  • anti-CTLA2, anti-PD1 , anti-PDL1 checkpoint inhibitors
  • other immune modifiers including but not limited to anti-OX40, and multiple other antineoplastic agents of multiple mechanisms.
  • Some aspects of the invention relate to the use of the compounds described herein or the composition described herein for use in the treatment of a disorder relating to the binding of a galectin to a ligand.
  • galectin is galectin-3,
  • Some aspects of the invention relate to the method of treating various disorders relating to the binding of a galectin to a ligand.
  • the methods comprise administering in a subject in need thereof a therapeutically effective amount of at least one compound described herein.
  • the subject in need thereof is a human having high levels of galectin-3.
  • Levels of galectin, for example galectin-3 can be quantified using any methods known in the art.
  • Some aspects of the invention relate to a method of treating diseases due to disruption in the activity of TGFbl (Transforming Growth Factor beta 1 ) by reversal of the Galectin-3 interaction with its receptor (TGFbl -Receptor) so as to recover normal regenerative activity in tissues.
  • TGFbl Transforming Growth Factor beta 1
  • Some aspects of the invention relate to a method of treating diseases associated with the Transforming Growth Factor Beta signaling pathway that involved many cellular and pathological processes in both the adult and embryo development including cell growth, cell differentiation, apoptosis, cellular homeostasis and other cellular functions.
  • Some aspects of the present invention relate to a method for treatment of a disorder relating to the binding of a Galectin, such as Galectin-3 binding to an Insulin-Receptor or TGFbl -receptor in a human, wherein the method comprises administering a therapeutically effective amount of at least one compound of formula (1 ), (2), (3), (4), (5), (6) or (7) or of Tables 1 -4 or a pharmaceutically acceptable salt or solvate thereof to a human in need thereof.
  • a Galectin such as Galectin-3 binding to an Insulin-Receptor or TGFbl -receptor in a human
  • the method comprises administering a therapeutically effective amount of at least one compound of formula (1 ), (2), (3), (4), (5), (6) or (7) or of Tables 1 -4 or a pharmaceutically acceptable salt or solvate thereof to a human in need thereof.
  • aspects of the invention relate to compounds, compositions and methods of treating various disorders in which lectin proteins play a role in the pathogenesis, including but not limited to treating systemic insulin resistance.
  • the compound can reverse galectin-3 binding to the insulin receptor and/or enhance sensitivity to insulin activity in various tissues.
  • aspects of the invention relate to compounds, compositions and methods for the treatment of, but not limited to, systemic insulin resistance.
  • the systemic insulin resistance is associated with obesity where elevated galectin-3 interacts with insulin receptor.
  • treatment with compounds of this invention can restore sensitivity to insulin activity in various tissues.
  • aspects of the invention relate to compounds, compositions and methods for the treatment of systemic insulin resistance associated with type 1 diabetes.
  • aspects of the invention relate to compounds, compositions and methods for the treatment of systemic insulin resistance associated with type 2 diabetes mellitus (T2DM).
  • T2DM type 2 diabetes mellitus
  • aspects of the invention relate to compounds, compositions and methods for the treatment of systemic insulin resistance associated with obesity, gestational diabetes and prediabetes.
  • the compound restores sensitivity of cells to insulin activity.
  • the compound inhibits galectin-3 interaction with Insulin receptor, which interferes with insulin binding and cellular glucose uptake mechanism.
  • aspects of the invention relate to compounds, compositions and methods for the treatment of low-grade inflammation, due to elevated levels of free fatty acid and triglycerides that cause insulin resistance in skeletal muscle and liver which contributes to the development of atherosclerotic vascular diseases and NAFLD.
  • aspects of the invention relate to compounds, compositions and methods for the treatment of polycystic ovarian syndrome (PCOS) associated with obesity, insulin resistance, and the compensatory hyperinsulinemia which affects some 85-70% of women with PCOS.
  • PCOS polycystic ovarian syndrome
  • aspects of the invention relate to compounds, compositions and methods for the treatment of diabetic nephropathy and glomerulosclerosis by attenuating integrin and ⁇ Receptor pathway in kidney chronic disease.
  • the compound can inhibit the overexpression of TGF receptor signaling system triggered by Insulin resistance in diabetic and cause decline in renal function, and can reverse the established lesions of diabetic glomerulopathy.
  • the compound is administered with a pharmaceutically acceptable adjuvant, excipient, formulation carrier or combinations thereof.
  • the compound is administered with an active agent and a pharmaceutically acceptable adjuvant, excipient, formulation carrier or combinations thereof.
  • the compound is administered with one or more anti diabetic drug.
  • administration of the compound of the present invention and the active agent produces a synergistic effect.
  • aspects of the invention relate to compounds, compositions and methods of treating systemic insulin resistance associated with obesity where elevated galectin-3 interacts with insulin receptor.
  • treatment with compounds of this invention can restore sensitivity to insulin activity in various tissues.
  • the compounds or compositions of the invention that bind to insulin receptor also identified as IR, INSR, CD220, HHF5.
  • Aspects of the invention relate to compounds, compositions and methods of treating diseases caused by disruption in the activity of TGFbl (Transforming Growth Factor beta 1 ).
  • the disorder is an inflammatory disorder, for example inflammatory bowel disease, Crohn's disease, multiple sclerosis, systemic lupus erythematosus, or ulcerative colitis.
  • inflammatory disorder for example inflammatory bowel disease, Crohn's disease, multiple sclerosis, systemic lupus erythematosus, or ulcerative colitis.
  • the disorder is fibrosis, for example liver fibrosis, pulmonary fibrosis, kidney fibrosis, heart fibrosis or fibrosis of any organ compromising the normal function of the organ.
  • the disorder is cancer.
  • the disorder is an autoimmune disease such as rheumatoid arthritis and multiple sclerosis.
  • the disorder is heart disease or heart failure.
  • the disorder is a metabolic disorder, for example diabetes.
  • the disorder relating is pathological angiogenesis, such as ocular angiogenesis, disease or conditions associated with ocular angiogenesis and cancer.
  • the composition or the compound can be used in the treatment of nonalcoholic steatohepatitis with or without liver fibrosis, inflammatory and autoimmune disorders, neoplastic conditions or cancers.
  • the composition can be used in the treatment of liver fibrosis, kidney fibrosis, lung fibrosis, or heart fibrosis.
  • the composition or the compound is capable of enhancing anti-fibrosis activity in organs, including but not limited to, liver, kidney, lung, and heart.
  • the composition or the compound can be used in treatment of inflammatory disorders of the vasculature including atherosclerosis and pulmonary hypertension.
  • the composition or the compound can be used in the treatment of heart disorders including heart failure, arrhythmias, and uremic cardiomyopathy.
  • the composition or the compound can be used in the treatment of kidney diseases including glomerulopathies and interstitial nephritis.
  • the composition or the compound can be used in the treatment of inflammatory, proliferative and fibrotic skin disorders including but not limited to psoriasis and scleroderma.
  • aspects of the invention relates to methods of treating allergic or atopic conditions, including but not limited to eczema, atopic dermatitis, or asthma.
  • aspects of the invention relates to methods of treating inflammatory and fibrotic disorders in which galectins are at least in part involved in the pathogenesis, by enhancing anti-fibrosis activity in organs, including but not limited to liver, kidney, lung, and heart.
  • aspects of the invention relates to methods relates to a composition or a compound that has a therapeutic activity to treat nonalcoholic steatohepatitis (NASH).
  • the invention elates to a method to reduce the pathology and disease activity associated with nonalcoholic steatohepatitis (NASH).
  • aspects of the invention relates to a composition or a compound used in treating or a method of treating inflammatory and autoimmune disorders in which galectins are at least in part involved in the pathogenesis including but not limited to arthritis, systemic lupus erythematosus, rheumatoid arthritis, asthma, and inflammatory bowel disease.
  • aspects of the invention relates to a composition or a compound to treat neoplastic conditions (e.g. benign or malignant neoplastic diseases) in which galectins are at least in part involved in the pathogenesis by inhibiting processes promoted by the increase in galectins.
  • neoplastic conditions e.g. benign or malignant neoplastic diseases
  • the invention relates a method of treating neoplastic conditions (e.g. benign or malignant neoplastic diseases) in which galectins are at least in part involved in the pathogenesis by inhibiting processes promoted by the increase in galectins.
  • the composition or a compound can be used to treat or prevent tumor cell growth, invasion, metastasis, and neovascularization.
  • the composition or a compound can be used to treat primary and secondary cancers.
  • the compound is a monomehc-selenium polyhydroxylated- cycloalkanes compound or a pharmaceutically acceptable salt or solvate thereof:
  • Z is a carbohydrate or linkage consisting of O, S, C, NH, CH2, Se, amino acid to R 2 and R 3 ;
  • W is selected from the group consisting of O, N, S, CH2, NH, and Se;
  • Y is selected from the group consisting of O, S, C, NH, CH2, Se, amino acid, and a combination thereof.
  • R 2 , and R 3 are independently selected from the group consisting of CO, S02, SO, P02, PO, CH, hydrogen, hydrophobic linear and cyclic hydrocarbons including heterocyclic substitutions of molecular weight of about 50-200 D.
  • the hydrophobic linear and cyclic hydrocarbons can comprise one of : a) an alkyl group of at least 4 carbons, an alkenyl group of at least 4 carbons, an alkyl group of at least 4 carbons substituted with a carboxy group, an alkenyl group of at least 4 carbons substituted with a carboxy group, an alkyl group of at least 4 carbons substituted with an amino group, an alkenyl group of at least 4 carbons substituted with an amino group, an alkyl group of at least 4 carbons substituted with both an amino and a carboxy group, an alkenyl group of at least 4 carbons substituted with both an amino and a carboxy group, and an alkyl group substituted with one or more halogens, b) a phenyl group substituted with at least one carboxy group, a phenyl group substituted with at least one halogen, a phenyl group substituted with at least one alkoxy group,
  • the compound is a dimeric-polyhydroxylated- cycloalkane compound.
  • the compound has the general or a pharmaceutically acceptable salt or solvate thereof:
  • X is Se, Se-Se or Se-S;
  • Z is independently selected from a carbohydrate (composing, for example, an oligomeric Se-galactoside) or linkage consisting of O, S, C, NH, CH2, Se, and amino acid to R 3 and R 4 ;
  • W is selected from the group consisting of O, N, S, CH2, NH, and Se;
  • Y is selected from the group consisting of O, S, C, NH, CH2, Se, and amino acid
  • R 2 , R3, and R 4 are independently selected from the group consisting of CO, S02, SO, P02, PO, CH, Hydrogen, and hydrophobic linear and cyclic hydrocarbons including heterocyclic substitutions of molecular weight of about 50- 200 D.
  • the hydrophobic linear and cyclic hydrocarbons can comprise one of : a) an alkyl group of at least 4 carbons, an alkenyl group of at least 4 carbons, an alkyl group of at least 4 carbons substituted with a carboxy group, an alkenyl group of at least 4 carbons substituted with a carboxy group, an alkyl group of at least 4 carbons substituted with an amino group, an alkenyl group of at least 4 carbons substituted with an amino group, an alkyl group of at least 4 carbons substituted with both an amino and a carboxy group, an alkenyl group of at least 4 carbons substituted with both an amino and a carboxy group, and an alkyl group substituted with one or more halogens, b) a phenyl group substituted with at least one carboxy group, a phenyl group substituted with at least one halogen, a phenyl group substituted with at least one alkoxy group,
  • X is Se, Se-Se or Se-S;
  • W is selected from the group consisting of O, N, S, CH2, NH, and Se;
  • Y, and Z are independently selected from the group consisting of O, S, C, NH, CH2, Se, and amino acid;
  • P and R 2 are independently selected from the group consisting of CO, S02, SO, P02, PO, CH, Hydrogen, hydrophobic linear and cyclic hydrocarbon including heterocyclic substitutions of molecular weight of 50-200 D including, but not limited to:
  • an alkyl group of at least 4 carbons an alkenyl group of at least 4 carbons, an alkyl group of at least 4 carbons substituted with a carboxy group, an alkenyl group of at least 4 carbons substituted with a carboxy group, an alkyl group of at least 4 carbons substituted with an amino group, an alkenyl group of at least 4 carbons substituted with an amino group, an alkyl group of at least 4 carbons substituted with both an amino and a carboxy group, an alkenyl group of at least 4 carbons substituted with both an amino and a carboxy group, and an alkyl group substituted with one or more halogens;
  • a phenyl group substituted with at least one car boxy group a phenyl group substituted with at least one halogen, a phenyl group substituted with at least one alkoxy group, a phenyl group substituted with at least one nitro group, a phenyl group substituted with at least one sulfo group, a phenyl group substituted with at least one amino group, a phenyl group substituted with at least one alkylamino group, a phenyl group substituted with at least one dialkylamino group, a phenyl group substituted with at least one hydroxy group, a phenyl group substituted with at least one carbonyl group and a phenyl group substituted with at least one substituted carbonyl group,
  • a naphthyl group a naphthyl group substituted with at least one carboxy group, a naphthyl group substituted with at least one halogen, a naphthyl group substituted with at least one alkoxy group, a naphthyl group substituted with at least one nitro group, a naphthyl group substituted with at least one sulfo group, a naphthyl group substituted with at least one amino group, a naphthyl group substituted with at least one alkylamino group, a naphthyl group substituted with at least one dialkylamino group, a naphthyl group substituted with at least one hydroxy group, a naphthyl group substituted with at least one carbonyl group and a naphthyl group substituted with at least one substituted carbonyl group; and
  • a heteroaryl group a heteroaryl group substituted with at least one carboxy group, a heteroaryl group substituted with at least one halogen, a heteroaryl group substituted with at least one alkoxy group, a heteroaryl group substituted with at least one nitro group, a heteroaryl group substituted with at least one sulfo group, a heteroaryl group substituted with at least one amino group, a heteroaryl group substituted with at least one alkylamino group, a heteroaryl group substituted with at least one dialkylamino group, a heteroaryl group substituted with at least one hydroxy group, a heteroaryl group substituted with at least one carbonyl group and a heteroaryl group substituted With at least one substituted carbonyl group,
  • a saccharide a substituted saccharide; D-galactose; substituted D-galactose; C3- [1 ,2,3]-triaZol-1 -yl-substituted D-galactose; hydrogen, an alkyl group, an alkenyl group, an aryl group, a heteroaryl group, and a heterocycle and derivatives; an amino group, a substituted amino group, an imino group, or a substituted imino group.
  • Example 1 Compound inhibition of Galectin binding to labeled probes
  • Fluorescein-labeled probes have been developed which bind to Galectin 3 and other Galectin proteins and these probes have been used to establish assays (FIGS. 5A & 5B) that measure the binding affinity of ligands for the Galectin proteins using Fluorescence Polarization (Sorme P, et al. Anal Biochem. 2004 Nov 1 ;334(1 ):36-47).
  • the IC50 is about from 5 nM to about 20 nM. In some embodiments, the IC50 is from about 5 nM to about 100 nM. In some embodiments, the IC50 is from about 10 nM to about 100 nM. In some embodiments, the IC50 is from about 50 nM to about 5 ⁇ . In some embodiments, the IC50 is from about 0.5 ⁇ to about 10 ⁇ . In some embodiments, the IC50 is from about 5 ⁇ to about 40 ⁇ .
  • G-625 a beta-D-Galactopyranoside, 3-deoxy-3-(4-(3-fluorophenyl)- 1 H-1 ,2,3-triazol-1 -yl)-beta-D-galactopyranosyl 3-deoxy-3-(4-(3-fluorophenyl)-1 H- 1 ,2,3-triazol-1 -yl)-1 -seleno-.
  • G-625 has single selenide bridge between two Aryl- triazole-galactosides, (see Table 2) has shown to inhibit the Gal-3 binding in the Fluorescent Polarization assay (FIG 7).
  • G-626 a beta-D-Galactopyranoside, 3-deoxy-3-(4-(3-fluorophenyl)- 1 H-1 ,2,3-triazol-1 -yl)-beta-D-galactopyranosyl 3-deoxy-3-(4-(3-fluorophenyl)-1 H- 1 ,2,3-triazol-1 -yl)-1 -seleno-.
  • G-625 has double selenide bridge between two Aryl- triazole-galactosides (see Table 2) has shown to inhibit the Gal-3 binding in the Fluorescent Polarization assay (FIG 7).
  • G-662 a seleno-monosaccharide was synthesized (see Table 1 ) and shown to inhibit the Gal-3 binding in the Fluorescent Polarization assay (FIG 7).
  • FRET assay fluorescent resonance energy transfer assays were developed for evaluating the interaction of Galectin proteins, including but not limited to Galectin-3, with a model fluorescent-labeled probe (see FIG. 5B).
  • compounds described herein avidly bind to Galectin-3, as well as other Galectin proteins, using this assay and displace the probe with high affinity, with IC 50 's (concentration at 50% inhibition) of between about 5 ⁇ to about 40 ⁇ .
  • the IC50 is about from 5 nM to about 20 nM. In some embodiments, the IC50 is from about 5 nM to about 100 nM.
  • the IC50 is from about 10 nM to about 100 nM. In some embodiments, the IC50 is from about 50 nM to about 5 ⁇ . In some embodiments, the IC50 is from about 0.5 ⁇ to about 10 ⁇ . In some embodiments, the IC50 is from about 5 ⁇ to about 40 ⁇ .
  • Example 3 Compound inhibition of galectin binding to physiologic ligands
  • Insulin resistance is a characteristic feature of patients with complications due to diabetes mellitus (T2DM) and is one of the defining clinical features in the Metabolic Syndrome (MetS), Mets is an array of biochemical and metabolic diseases that estimate to effect over 20 % of adults (>20 years old) in the United States or approximately 50 million Americans. As the epidemic of obesity shows no signs of reversing, this number is likely to rise dramatically in the future.
  • T2DM diabetes mellitus
  • MetS Metabolic Syndrome
  • Insulin is a hormone which has diverse functions including stimulation of nutrient transport into cells, regulation of variety of enzymatic activity and regulation of energy homeostasis. These functions involve glucose metabolism through intracellular signaling pathways in the liver, adipose tissue and muscles. I. In the liver, insulin resistance leads to elevated hepatic glucose production. In adipose tissue insulin resistance affecting lipase activity leading to anti-lipolytic effecting free fatty acid efflux out of adipocytes and increasing circulating free fatty acids.
  • Galectin-3 known to be mainly secreted by macrophages, may play a crucial role in this inflammation process thus it links inflammation to decreased in insulin sensitivity. Inhibition of Galectin-3 could be a new drug target to treat insulin resistance.
  • Insulin receptor and insulin interaction is checkpoint for a second pathway, the Ras-mitogen-activated protein kinase (MAPK) which mediates gene expression, and also affects the PI3K-AKT pathway that control cell growth and differentiation.
  • Insulin receptor substrate is the common intermediate, which include four distinct family members, IRS1 -4. Defects in insulin signaling typically involve insulin receptor substrate- 1 (IRS1 ). Activation of the insulin receptor increase tyrosine phosphorylation of IRS1 which initiate signal transduction. However, when serine 307 is phosphorylated, signaling is diminished.
  • Additional inflammation- related negative regulators of IR or IRS1 including the suppressor of cytokine signaling (Socs) may promote ubiquitylation, where ubiquitin, a small protein, is attached to another targeted protein changing their functionality and subsequent degradation, e.g. IRS inactivation.
  • G-625 - a beta-D-Galactopyranoside, 3-deoxy-3-(4-(3- fluorophenyl)-1 H-1 ,2,3-triazol-1 -yl)-beta-D-galactopyranosyl 3-deoxy-3-(4-(3- fluorophenyl)-1 H-1 ,2,3-triazol-1 -yl)-1 -seleno-.
  • G-625 has single selenide bridge between two Aryl-triazole-galactosides (see Table 2), has showed an inhibitory activity in the insulin receptor - galectin-3 interaction (FIG. 8).
  • G-662 a seleno-monosaccharide was synthesized (see Table 1 ) and showed an inhibitory activity in the insulin receptor - galectin-3 interaction (FIG. 8).
  • G-625 - a beta-D-Galactopyranoside, 3-deoxy-3-(4-(3- fluorophenyl)-1 H-1 ,2,3-triazol-1 -yl)-beta-D-galactopyranosyl 3-deoxy-3-(4-(3- fluorophenyl)-1 H-1 ,2,3-triazol-1 -yl)-1 -seleno-.
  • G-625 has single selenide bridge between two Aryl-triazole-galactosides (see Table 2), has showed an inhibitory activity in the TGF- ⁇ receptor - galectin-3 (FIG. 9).
  • G-662 a seleno-monosaccharide was synthesized (see Table 1 ), showed an inhibitory activity in the TGF- ⁇ receptor - galectin-3 interaction (FIG. 9).
  • Example 4 Compound binding to amino acid residues in galectin proteins
  • Heteronuclear NMR spectroscopy is used to evaluate the interaction of compounds described herein with galectin molecules, including but not limited to galectin-3, to assess the interaction residues on the galectin-3 molecule.
  • NMR experiments are carried out at 30°C on Bruker 600 MHz, 700 MHz or 850 MHz spectrometers equipped with H/C/N triple-resonance probes and x/y/z triple-axis pulse field gradient units.
  • a gradient sensitivity-enhanced version of two-dimensional 1 H- 15 N HSQC is applied with 256 (f1 ) x 2048 (t2) complex data points in nitrogen and proton dimensions, respectively.
  • Raw data are converted and processed by using NMRPipe and were analyzed by using NMRview.
  • Example 5 Cellular activity of cytokine activity related to galectin binding inhibition
  • Example 1 describes the ability of compounds of this application to inhibit the binding of physiologic ligands to galectin molecules. In the experiments of this example, the functional implications of those binding interactions were evaluated. [00246] One of the interactions with galectin-3 that is inhibited by the compounds described herein was TGF- ⁇ receptor. Therefore, experiments were done to evaluate the effect of compounds on TGR- ⁇ receptor activity in cell lines. Various TGF- ⁇ responsive cell lines, including but not limited to LX-2 and THP-1 cells, were treated with TGF- ⁇ and response of the cells was measured by looking at activation of second messenger systems, including but not limited to phosphorylation of various intracellular SMAD proteins.
  • MCF-7 cells were resuspended in culture media containing 4X Pen/Strep and 0.25% Fetal Bovine Serum (Gibco lot* 1202161 ).
  • Tested compound was diluted serially in assay media as above, usually at a range of 100 ⁇ g/ml to 20 ng/mL
  • HTB-38 cells were resuspended in culture media containing 8 ng/ml h-IFN- gamma, 4X Pen/Strep and 10% Fetal Bovine Serum (Gibco lot# 1260930).
  • Tested compound was diluted serially in assay media as above, usually in range of 100 ⁇ g/ml to 20 ng/mL
  • Example 1 Cellular motility assays are performed to evaluate the physiological significance of inhibiting the interaction of galectin-3 with various integrin and other cell surface molecules defined in Example 1 .
  • Cellular studies are performed using multiple cell lines in a semi-permeable membrane separated well apparatus. Treatment of cells with compounds described herein is found to inhibit cellular motility, confirming that the binding interaction inhibition described in Example 1 has a physiological role in cellular models.
  • Example 6 ln-vitro Inflammatory Model (a monocyte based assay)
  • a model of macrophage polarization was set up, starting from THP-1 monocytes culture which is differentiated into inflammatory macrophages using PMA (Phorbol 12-myristate 13-acetate) for 2-4 days. Once differentiated (M0 macrophages), the macrophages were induced with LPS or LPS and IFN-gamma for macrophage activation (M1 ) to inflammatory stage for 1 -3 days. Array of cytokines and chemokines were analyzed to confirm the polarization of THP-1 -derived macrophages to inflammatory stage.
  • PMA Phorbol 12-myristate 13-acetate
  • the impact of the anti-galectin 3 compounds on macrophage polarization was assessed first by monitoring cell viability using a colorimetric method (using a tetrazolium reagent) to determine the number of viable cells in proliferation or cytotoxicity assays (Promega, The CellTiter 96® AQueous One Solution Cell Proliferation Assay which contains a novel tetrazolium compound [3-(4,5-dimethyl-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt; MTS] and an electron coupling reagent (phenazine ethosulfate; PES)) and inflammatory stage evaluated by a quantitatively measure of the chemokine Monocyte Chemoattractant Protein-1 (MCP-1 / CCL2), a key protein that regulates migration and infiltration of monocytes/macrophages in cellular process of inflammation.
  • THP-1 cells were stimulated by microbial endotoxin which transforms the cells to inflammatory macrophages (M1 ) which secret inflammatory cytokines like Monocyte Chemoattractant Protein-1 (MCP-1 ).
  • M1 macrophages
  • MCP-1 Monocyte Chemoattractant Protein-1
  • THP-1 cells were cultured in media containing Gentamicin
  • THP-1 cells are transfer to wells in a 96 well plate 2,000 cells/well for 2 days incubation in assay media containing 10 ng/ml PMA
  • Compounds described herein are evaluated for physicochemical properties, including but not limited to solubility (Thermodynamic and Kinetic method), various pH changes, solubility in biorelevant medium (FaSSIF, FaSSGF, FeSSI F), Log D (Octanol/water and Cyclohexane/water), chemical stability in plasma, and blood partitioning.
  • solubility Thermodynamic and Kinetic method
  • biorelevant medium FaSSIF, FaSSGF, FeSSI F
  • Log D Octanol/water and Cyclohexane/water
  • chemical stability in plasma and blood partitioning.
  • [QQ256] Compounds described herein are evaluated for animal pharmacokinetic properties, including but not limited to pharmacokinetics by various routes viz. , oral, intravenous, intraperitoneal, subcutaneous in mice (Swiss Albino, C57, Balb/C), rats (Wistar, Sprague Dawley), rabbits (New Zealand white), dogs (Beagle), Cynomolgus monkeys, etc. , tissue distribution, brain to plasma ratio, biliary excretion, and mass balance.
  • routes viz. , oral, intravenous, intraperitoneal, subcutaneous in mice (Swiss Albino, C57, Balb/C), rats (Wistar, Sprague Dawley), rabbits (New Zealand white), dogs (Beagle), Cynomolgus monkeys, etc. , tissue distribution, brain to plasma ratio, biliary excretion, and mass balance.
  • Compounds described herein are evaluated for protein binding, including but not limited to plasma protein binding (ultra-Filtration and Equilibrium Dialysis) and microsomal protein binding.
  • Compounds described herein are evaluated for in vitro metabolism, including but not limited to cytochrome P450 inhibition, cytochrome P450 time dependent inhibition, metabolic stability, liver microsome metabolism, S-9 fraction metabolism, effect on cryopreserved hepatocyte, plasma stability, and GSH trapping.
  • Compounds described herein are evaluated for metabolite identification, including but not limited to identification in vitro (microsomes, S9 and hepatocytes) and in vivo samples.
  • Example 9 Cell culture adipocyte model
  • 3T3-L1 adipocytes were cultured with various doses of insulin (10 nM to 100 nM) to cause chronic insulin exposure or 0.1 M to 1 M dexamethasone (DEX) for 8 to 24h at 37 °C or with 1 to 20 ng/ml TNF at 37 °C for 48 h in full DMEM medium. The medium was replaced twice a day with fresh medium containing TNF. After insulin resistance treatment, cells were washed and then serum starved for 1 -2 h prior to insulin stimulation and assessment of insulin- regulated kinases and processes. It has been previously shown that this protocol is adequate to return the cells to their baseline level of GLUT4 translocation (Hoehn, K.
  • the cell pellet was resuspended in 1 1 ml of MM.
  • the cells were plated at 20,000 cells per 100 ⁇ in a 96-well plate.
  • 3T3L1 adipocytes were assayed as follows:
  • Luminescence was recorded with 0.3-1 second integration on a luminometer to evaluate the cellular effect of Galectin-3 on glucose uptake.
  • adipocytes cells Differentiation of adipocytes cells was monitored by various well- defined insulin related activation markers, including expression of Insulin Receptor (IR) and its activation by insulin, but not limited to IR kinase activity within minutes of exposing to insulin. Inhibition of this insulin activation by treatment with Galectin-3. The effect of Galectin-3 on IR was monitored also by rate of glucose uptake.
  • IR Insulin Receptor
  • the G-625 compound was synthesized using the following scheme (see FIG. 4)
  • Step-1
  • reaction mixture was stirred at room temperature for 16 h. After completion, the reaction mixture was quenched with water (20 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were filtered through a pad of celite bed, washed with EtOAc, dried (Na 2 S0 4 ) and concentrated in vacuo and the residue was washed with Et 2 0 (10 mL) to afford the title compound (7) as a white solid (164 mg, 94%).

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