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WO2012019071A1 - Méthodes de traitement prophylactique et thérapeutique de la sarcopénie - Google Patents

Méthodes de traitement prophylactique et thérapeutique de la sarcopénie Download PDF

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Publication number
WO2012019071A1
WO2012019071A1 PCT/US2011/046693 US2011046693W WO2012019071A1 WO 2012019071 A1 WO2012019071 A1 WO 2012019071A1 US 2011046693 W US2011046693 W US 2011046693W WO 2012019071 A1 WO2012019071 A1 WO 2012019071A1
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Prior art keywords
alkyl
aryl
cycloalkyl
heterocyclyl
alkenyl
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PCT/US2011/046693
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English (en)
Inventor
Andrew R. Marks
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The Trustees Of Columbia University In The City Of New York
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Publication of WO2012019071A1 publication Critical patent/WO2012019071A1/fr

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    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system

Definitions

  • the invention relates to compositions and methods of preventing and treating sarcopenia.
  • SR Ca 2+ release channel also known in skeletal muscle as the ryanodine receptor 1 (RyRl).
  • RyRl sarcoplasmic reticulum
  • the release of SR Ca 2+ via RyRl raises cytoplasmic [Ca 2+ ] cyt leading to activation of actin- myosin cross-bridging and shortening of the sarcomere, manifesting as muscle contraction.
  • Impaired Ca 2+ handling is associated with contractile dysfunction in heart failure and muscular dystrophy, and sarcopenic skeletal muscle is reported to have decreased SR Ca 2+ release.
  • proper Ca 2+ handling in muscle plays a key role in normal EC coupling and specific force production.
  • SNO Cysteine nitrosylation
  • carbonyl modifications of proteins are emerging as important cellular mediators for RyR function and Ca 2+ signaling.
  • Excessive SNO- modification of RyRl disrupts the interaction between RyRl and calstabinl (also known as FKBP12 in skeletal muscle). Loss of the RyRl /Calstabinl interaction results in channels that leak SR Ca 2+ . This leak leads to reduced SR Ca 2+ release and muscle function.
  • sarcopenia Currently, the primary treatment for sarcopenia is exercise. Specifically, resistance training or strength training— exercises that increase muscle strength and endurance with weights or resistance bands— are shown to be beneficial for both the prevention and treatment of sarcopenia. Resistance training is reported to positively influence the neuromuscular system, hormone concentrations, and protein synthesis rate. Research show that an exercise program of progressive resistance training can increase protein synthesis rates in the elderly in as little as two weeks. While this is possible for patients who are otherwise generally in good health and capable of conducting such exercise, it is not possible for a certain segment of the population to continually and properly follow an exercise regimen.
  • compositions and methods useful for the treatment and/or prevention of sarcopenia involve modulation of the function of skeletal muscle ryanodine receptors (RyRl).
  • the present invention provides a method for treating and/or preventing sarcopenia, in part, based on the discovery that administering certain
  • benzothiazepine, benzoxazepine, benzodiazepine and benzazepine compounds to aged subjects, exemplified by mice, improves muscle function and exercise capacity by correcting defects at the level of the myocyte Ca 2+ handling machinery.
  • the present invention provides a method of treating and/or preventing sarcopenia in a subject in need thereof, comprising administering to the subject a therapeutically or prophylactically effective amount of a compound of Formula I, I-a', I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-i, I-j, I-k, 1-1, 1-m, I-n, I-o, I-p, I-a-1, 1-b-1, 1-c-1, 1-d-1, I-e-1, I-f- 1 , 1-g-1, I-h- 1 , I-i- 1 , or Formula II, or enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, hydrates, solvates, complexes, metabolites, or pro-drugs thereof, or any combination thereof.
  • the structures of these Formulae are provided in the Detailed Description that follows.
  • the present invention provides a method of treating or preventing sarcopenia in a subject in need thereof, comprising administering to the subject a therapeutically or prophylactically effective amount of a compound represented by the structure of Formula I-k as disclosed herein.
  • the present invention provides a method of treating or preventing sarcopenia in a subject in need thereof, comprising administering to the subject a therapeutically or prophylactically effective amount of the compound Si l l represented by the structure:
  • the present invention provides a method of treating or preventing sarcopenia in a subject in need thereof, comprising administering to the subject a therapeutically or prophylactically effective amount of a compound represented by the structure of Formula I-o as disclosed herein.
  • the present invention provides a method of treating or preventing cardiac ischemia/reperfusion injury in a subject in need thereof, comprising administering to the subject a therapeutically or prophylactically effective amount of the com ound SI 07 represented by the structure
  • a preferred salt is the hydrochloride salt (S107-HC1).
  • the present invention provides a method of treating or preventing cardiac ischemia/reperfusion injury in a subject in need thereof, comprising administering to the subject a therapeutically or prophylactically effective amount of the compound S36 represented by the structure
  • a referred salt is the sodium salt (S36-Na) represented by the structure
  • the present invention provides a method of treating or preventing sarcopenia in a subject in need thereof, comprising administering to the subject a therapeutically or prophylactically effective amount of a compound represented by the structure of Formula I, I-a', I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-i, I-j, I-k, I-l, I-m, I-n, I-o, I-p, I-a-1, I-b- 1 , 1-c-1, I-d- 1 , 1-e-1, I-f- 1 , 1-g-1, I-h- 1 , I-i- 1 , or Formula II, or enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, hydrates, solvates, complexes, metabolites, or pro-drugs thereof, or any combination thereof.
  • the compound administered is selected from the group consisting of SI, S2, S3, S4, S5, S6, S7, S9, SI 1, S12, SI 3, S14, SI 9, S20, S22, S23, S24, S25, S26, S27, S36, S37, S38, S40, S43, S44, S45, S46, S47, S48, S49, S50, S51, S52, S53, S54, S55, S56, S57, S58, S59, S60, S61, S62, S63, S64, S66, S67, S68, S69, S70, S71, S72, S73, S74, S75, S76, S77, S78, S79, S80, S81, S82, S83, S84, S85, S86, S87, S88, S89, S90, S91, S92, S93, S94, S95, S96, S97, S98, S99, S100, S101, S
  • the present invention provides a method of treating and/or preventing sarcopenia in a subject in need thereof, comprising administering to the subject a therapeutically or prophylactically effective amount of a compound that decreases the open probability of the RyRl channel under conditions that simulate resting muscle (i.e., low activating calcium levels).
  • the present invention provides a method of treating and/or preventing sarcopenia in a subject in need thereof, comprising administering to the subject a therapeutically or prophylactically effective amount of a compound that decreases Ca 2+ current through the RyRl channel under conditions that simulate resting muscle (i.e., low activating calcium levels).
  • the present invention provides a method of treating and/or preventing sarcopenia in a subject in need thereof, comprising administering to the subject a therapeutically or prophylactically effective amount of a compound that decreases calcium leak through the RyRl channel under conditions that simulate resting muscle (i.e., low activating calcium levels).
  • the present invention provides a method of treating and/or preventing sarcopenia in a subject in need thereof, comprising administering to the subject a therapeutically or prophylactically effective amount of a compound that increases the affinity with which calstabin 1 binds to nitrosylated, and/or oxidized, and/or phosphorylated, RyRl .
  • the present invention provides a method of treating and/or preventing sarcopenia in a subject in need thereof, comprising administering to the subject a therapeutically or prophylactically effective amount of a compound that decreases dissociation of calstabin 1 from nitrosylated, and/or oxidized, and/or phosphorylated, RyRl .
  • the present invention provides a method of treating and/or preventing sarcopenia in a subject in need thereof, comprising administering to the subject a therapeutically or prophylactically effective amount of a compound that increases rebinding of calstabin 1 to nitrosylated, and/or oxidized, and/or phosphorylated, RyRl .
  • the subject to whom the compounds of the invention are administered is a mammal selected from the group consisting of primates, rodents, ovine species, bovine species, porcine species, equine species, feline species and canine species.
  • the subject is a human, preferably over the age of 60, more preferably over the age of 70, and most preferably over the age of 80.
  • the older a person the greater tendency is for that person to be subject to sarcopenia and thus the need is greater for administration of one of the compounds disclosed herein to reduce or prevent further muscle deterioration.
  • the compounds of the invention may be administered by any suitable route known in the art, without limitation.
  • compounds of the invention may be administered by a route selected from the group consisting of parenteral, enteral, intravenous, intraarterial, intracardiac, intra intrapericardial, intraosseal, intracutaneous, subcutaneous, intradermal, subdermal, transdermal, intrathecal, intramuscular, intraperitoneal, intrasternal,
  • parenchymatous oral, sublingual, buccal, rectal, vaginal, inhalational, and intranasal.
  • the compounds of the invention may be administered using a drug-releasing implant.
  • the compounds of the invention are administered to the subject at a dose of from about 0.01 mg/kg/day to about 20 mg/kg/day, or more preferably still, at a dose of from about 0.05 mg/kg/day to about 1 mg/kg/day.
  • a dose of from about 0.01 mg/kg/day to about 20 mg/kg/day or more preferably still, at a dose of from about 0.05 mg/kg/day to about 1 mg/kg/day.
  • Other suitable dose ranges are provided in the Detailed Description and Examples.
  • one of skill in the art can select other suitable doses for administration.
  • the invention provides use of a compound of Formula I, I-a', I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-i, I-j, I-k, I-l, I-m, I-n, I-o, I-p, I-a-1, I-b- 1 , 1- c-1, I-d- 1 , 1-e-1, I-f- 1 , 1-g-1, I-h- 1 , I-i- 1 , or Formula II for preparation of a medicament for treating or preventing sarcopenia in a subject in need thereof. All compounds disclosed herein are expected to be useful for treating or preventing sarcopenia in a subject in need thereof.
  • Figures 1 A-H show impaired force development and reduced Ca 2+ release in aged extensor digitorum longus (EDL) muscle.
  • Figures 2A-D show effects of SR Ca 2+ leak on mitochondrial membrane potential, ROS and RNS production in skeletal muscle fibers.
  • Figures 3A-G show improved exercise capacity, muscle specific force, and increased calstabinl in the RyRl complex following SI 07 treatment of aged mice.
  • Figures 4A-E show that SI 07 reduces SR Ca 2+ leak resulting in enhanced tetanic SR Ca 2+ release in skeletal muscle from aged mice.
  • Figures 6A-H show that improved muscle function and exercise capacity following SI 07 treatment of aged mice requires calstabinl .
  • Figures 7A-E represent a model of RyRl -mediated SR Ca 2+ leak and mitochondrial dysfunction in aging skeletal muscle.
  • Figures 8A and B show oxidative stress in muscle from aged WT mice and muscle- specific calstabinl KO mice and effects of treatment with SI 07.
  • Figures 9A-F show that RyRl from aged rat skeletal muscle are cysteine-nitrosylated, oxidized and depleted of calstabinl .
  • Figures 10A-E show electron microscopy of EDL muscle.
  • Figures 11A-E show mitochondrial uptake of the Ca 2+ indicator Rhod-2 AM in flexor digitorum brevis (FDB) muscle fiber.
  • Figure 12 shows EDL muscle fiber cross-sectional area in aged mice is not altered by 4 weeks of SI 07 treatment.
  • Figures 13A-C show increased open probability of RyRl-S2844D channels.
  • FIGS 14A-C show strategy used to generate RyRl-S2844D mice. DETAILED DESCRIPTION OF THE INVENTION
  • rycal compounds refers to compounds of the general Formula I, I-a', I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-i, I-j, I-k, 1-1, 1-m, I-n, I-o, I-p, I-a-1, 1-b-1, I-c-1, I-d- 1 , 1-e-1, I-f- 1 , 1-g-1, I-h- 1 , I-i- 1 , or Formula II, as provided by the invention, and herein referred to as "compound(s) of the invention".
  • the compounds of the invention are referred using a numerical naming system, with compound numbers 1 to 477 provided herein. These numbered compounds are referred to using either the prefix "S.” Thus, the first numbered compound is referred to either as “SI”, the second numbered compound is referred to as either “S2”, the third numbered compound is referred to as either "S3”, and so on.
  • S nomenclature systems is used interchangeably throughout the specification, the drawings, and the claims to indicate the specific compounds that are shown by their structures in the Detailed Description.
  • alkyl refers to a linear or branched, saturated hydrocarbon and preferably one having from 1 to 6 carbon atoms.
  • Representative alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, and neohexyl.
  • alkenyl refers to a linear or branched hydrocarbon and preferably one having from 2 to 6 carbon atoms and having at least one carbon-carbon double bond. In one embodiment, the alkenyl has one or two double bonds. The double bond may exist as the E or Z isomers and the compounds of the present invention include both isomers.
  • alkynyl refers to a linear or branched hydrocarbon and preferably one having from 2 to 6 carbon atoms and having at least one carbon-carbon triple bond.
  • aryl refers to an aromatic group and preferably one containing 1 to 3 aromatic rings, either fused or linked. An example of an aryl group is a phenyl group.
  • cyclic group as used herein includes a cycloalkyl group and a heterocyclic group.
  • cycloalkyl group refers to a three- to seven-membered saturated or partially unsaturated carbon ring. Any suitable ring position of the cycloalkyl group may be covalently linked to the defined chemical structure. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • halogen refers to fluorine, chlorine, bromine, and iodine.
  • heterocyclic group or “heterocyclic” or “heterocyclyl” or “heterocyclo” as used herein refers to fully saturated, or partially or fully unsaturated, including aromatic (i.e., “heteroaryl”) cyclic groups (for example, 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 16 membered tricyclic ring systems) which have at least one heteroatom in at least one carbon atom-containing ring.
  • aromatic i.e., "heteroaryl”
  • Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3, or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quatemized.
  • the heterocyclic group may be attached to the remainder of the molecule at any heteroatom or carbon atom of the ring or ring system.
  • heterocyclic groups include, but are not limited to, azepanyl, azetidinyl, aziridinyl, dioxolanyl, furanyl, furazanyl, homo piperazinyl, imidazolidinyl, imidazolinyl, isothiazolyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyrimidinyl,
  • bicyclic heterocyclic groups include indolyl, isoindolyl, benzothiazolyl, benzoxazolyl,
  • triazinylazepinyl tetrahydroquinolinyl and the like.
  • tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl and the like.
  • phenyl as used herein includes a substituted or unsubstituted phenyl group.
  • alkyl alkenyl
  • alkynyl alkynyl
  • aryl alkenyl
  • aryl acyl
  • phenyl cyclic group
  • cycloalkyl heterocyclyl
  • heterocyclo heterocyclo
  • heterocycle substituents
  • groups such as alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, alkylaryl, heteroaryl, heterocycle and aryl can themselves be optionally substituted.
  • Representative substituents may further optionally include at least one labeling group, such as a fluorescent, a bioluminescent, a chemiluminescent, a colorimetric or a radioactive labeling group.
  • a fluorescent labeling group can be selected from bodipy, dansyl, fluorescein, rhodamine, Texas red, cyanine dyes, pyrene, coumarins, Cascade BlueTM, Pacific Blue, Marina Blue, Oregon Green, 4',6-Diamidino-2-phenylindole (DAPI), indopyra dyes, lucifer yellow, propidium iodide, porphyrins, arginine, and variants and derivatives thereof.
  • DAPI 6-Diamidino-2-phenylindole
  • SI 18 of the present invention contains a labeling group BODIPY, which is a family of fiuorophores based on the 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene moiety.
  • BODIPY is a family of fiuorophores based on the 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene moiety.
  • fluorescent label moieties and fluorescence techniques see, e.g., Handbook of Fluorescent Probes and Research Chemicals, by Richard P. Haughland, Sixth Edition, Molecular Probes, (1996), which is hereby incorporated by reference in its entirety.
  • One of skill in the art can readily select a suitable labeling group, and conjugate such a labeling group to any of the compounds of the invention, without undue experimentation.
  • quaternary nitrogen refers to a tetravalent positively charged nitrogen atom including, for example, the positively charged nitrogen in a tetraalkylammonium group (e.g., tetramethylammonium, N-methylpyridinium), the positively charged nitrogen in protonated ammonium species (e.g., trimethyl-hydroammonium, N-hydropyridinium), the positively charged nitrogen in amine N-oxides (e.g., N-methyl-morpholine-N-oxide, pyridine-N-oxide), and the positively charged nitrogen in an N-amino-ammonium group (e.g.,
  • the compounds described herein may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention.
  • prodrug denotes a compound that, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield compounds of the present invention.
  • an ester may be a prodrug of the corresponding carboxylic acid.
  • compound(s) of the invention means a compound of Formula I, I-a', I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-i, I-j, I-k, I-l, I-m, I-n, I-o, I-p, I-a-1, I-b- 1 , I-c-1, I-d- 1 , 1-e-1, I-f- 1 , 1-g-1, I-h- 1 , I-i- 1 , or Formula II, or any of the specific chemical compounds described herein, and salts, hydrates, complexes, metabolites, prodrugs and solvates thereof, or any combination thereof, such as may be used for the treatment or prevention of sarcopenia.
  • a “pharmaceutical composition” refers to a mixture of one or more of the compounds described herein, or pharmaceutically acceptable salts, hydrates or pro-drugs thereof, with other chemical components, such as physiologically acceptable carriers and excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism or subject.
  • a “pro-drug” refers to an agent which is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they are easier to administer than the parent drug. They are bioavailable, for instance, by oral administration whereas the parent drug is not. The pro-drug also has improved solubility in pharmaceutical compositions over the parent drug.
  • the compound carries protective groups which are split off by hydrolysis in body fluids, e.g., in the bloodstream, thus releasing active compound or is oxidized or reduced in body fluids to release the compound.
  • a compound of the present invention also can be formulated as a pharmaceutically acceptable salt, e.g., acid addition salt, and complexes thereof.
  • the preparation of such salts can facilitate the pharmacological use by altering the physical characteristics of the agent without preventing its physiological effect.
  • useful alterations in physical properties include, but are not limited to, lowering the melting point to facilitate transmucosal administration and increasing the solubility to facilitate administering higher concentrations of the drug.
  • salts means a salt that is suitable for, or compatible with, the treatment of a patient or a subject such as a human patient.
  • the salts can be any non-toxic organic or inorganic salt of any of the compounds represented by Formula I, I-a', I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-i, I-j, I-k, 1-1, 1-m, I-n, I-o, I-p, I-a-1, 1-b-1, 1-c-1, 1-d-1, I-e-1, I-f- 1 , 1-g-1, I-h- 1 , I-i- 1 , or Formula II, or any of the specific compounds described herein, or any of their intermediates.
  • Illustrative salt-forming ions include, but are not limited to, ammonium (NH 4 ), calcium (Ca ), iron (Fe and Fe ), magnesium (Mg ), potassium (K + ), pyridinium (C 5 H 5 NH + ), quaternary ammonium (NR 4 + ), sodium (Na + ), acetate, carbonate, chloride, bromide, citrate, cyanide, hydroxide, nitrate, nitrite, oxide, phosphate, sulfate, maleate, fumarate, lactate, tartrate, gluconate, besylate, and valproate.
  • Illustrative inorganic acids that form suitable salts include, but are not limited to, hydrochloric, hydrobromic, sulfuric and phosphoric acids, as well as metal salts such as sodium monohydrogen
  • the acid addition salts of compounds of Formula I, I-a', I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-i, I-j, I-k, 1-1, 1-m, I-n, I-o, I-p, I-a-1, I-b- 1 , 1-c-1, I-d- 1 , I-e-1, 1-f-1, 1-g-1, I-h- 1 , 1-i-1, or Formula II are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms.
  • the selection of an appropriate salt can be performed by one skilled in the art.
  • salts in reference to "Handbook of Pharmaceutical Salts : Properties, Selection, and Use” by P. Heinrich Stahl and Camille G. Wermuth, or Berge (1977) "Pharmaceutcial Salts” J. Pharm Sci., Vol 66(1), p 1-19.
  • Other non-pharmaceutically acceptable salts ⁇ e.g., oxalates
  • a compound of the present invention when a compound of the present invention is a racemate, the racemate can be separated into the (S)-compound and (R)-compound by optical resolution.
  • Individual optical isomers and mixtures thereof are included in the scope of Formula I, I-a', I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-i, I-j, I-k, 1-1, 1-m, I-n, I-o, I-p, I-a-1 , I-b- 1 , I-c-1 , 1-d-1 , 1-e-1 , I-f- 1 , 1-g-1 , 1-h-1 , I-i-1 , or Formula II.
  • an “effective amount,” “sufficient amount,” “therapeutically effective amount,” or “prophylactically effective amount” of an agent or compounds, as used herein, refer to amounts sufficient to effect the beneficial or desired results, including clinical results and, as such, the actual “amount” intended will depend upon the context in which it is being applied, such as whether the desired clinical outcome is prevention or treatment.
  • the term "effective amount” also includes that amount of the compound of Formula I, I-a', I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-i, I-j, I-k, 1-1, 1-m, I-n, I-o, I-p, I-a-1 , 1-b-1 , I-c-1 , 1-d-1 , 1-e-1 , I-f- 1 , I-g-1 , I-h- 1 , I-i-1 , or Formula II, which is "therapeutically effective” or “prophylactically effective” and which avoids or substantially attenuates undesirable side effects.
  • treatment is an approach for obtaining beneficial or desired results, including clinical results.
  • beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state and remission (whether partial or total), whether detectable or undetectable.
  • Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment. Unless otherwise stated, the term “treatment” should be construed as encompassing preventive and therapeutic methods.
  • animal refers to all members of the animal kingdom including, but not limited to, mammals, animals (e.g., cats, dogs, horses, etc.) and humans.
  • All stereoisomers of the compounds of the present invention are contemplated within the scope of this invention.
  • Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers (e.g., as a pure or substantially pure optical isomer having a specified activity), or may be admixed, for example, as racemates or with all other, or other selected,
  • the chiral centers of the present invention may have the S or R configuration as defined by the IUPAC 1974 Recommendations.
  • the racemic forms can be resolved by physical methods, such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by chiral column chromatography.
  • the individual optical isomers can be obtained from the racemates by any suitable method, including without limitation, conventional methods, such as, for example, salt formation with an optically active acid followed by crystallization.
  • Compounds of the present invention are, subsequent to their preparation, preferably isolated and purified to obtain a composition containing an amount by weight equal to or greater than 99% of the compound ("substantially pure” compound), which is then used or formulated as described herein. Such “substantially pure” compounds of the present invention are also contemplated herein as part of the present invention.
  • FKBP12 channel stabilizing subunit FK506 binding protein
  • This remodeling of the RyRl channel complex results in "leaky” channels manifested by increased Ca 2+ sparks.
  • skeletal muscle tetanic Ca 2+ and muscle specific force are significantly reduced in 2 yr old mice (equivalent to -70-80 yr old humans).
  • the present invention provides compositions and methods that are useful for treating and/or preventing sarcopenia. More particularly, the present invention provides compositions comprising the compounds described herein, and methods of treatment and/or prevention comprising administration of these compositions to subjects suffering from, or at risk of developing sarcopenia.
  • compositions described herein are administered therapeutically or prophylactically to subjects who are suffering from, or at risk of developing sarcopenia.
  • a subject may be any animal that is suffering from, or at risk of developing sarcopenia.
  • the subject is a mammal.
  • mammals that may be treated using the methods and compositions of the invention include, but are not limited to, primates, rodents, ovine species, bovine species, porcine species, equine species, feline species and canine species.
  • Symptoms of muscle loss include musculoskeletal weakness and loss of stamina, which can interfere with physical activities, which in turn, results in further reductions in muscle mass.
  • sarcopenia is mostly seen in people who are inactive, the fact that it also occurs in people who stay physically active throughout life suggests there are other factors involved in the development of this condition.
  • the "subjects" of the present invention may also be in vitro or in vivo systems, including, without limitation, isolated or cultured cells or tissues, in vitro assay systems.
  • compositions for preparing and/or preparing the compounds described herein may be formulated into compositions for preparing and/or preparing the compounds described herein.
  • compositions comprise one or more of the benzothiazepine, benzoxazepine, benzodiazepine and benzazepine compounds described herein (such as the compounds of Formula I, I-a', I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-i, I-j, I-k, 1-1, 1-m, I-n, I-o, I-p, I-a-1, 1-b-1, 1-c-1, 1-d-1, 1-e-1, I-f-1, 1-g-1, 1-h-1, 1-i-1, or Formula II), in admixture with a pharmaceutically acceptable diluent and/or carrier and optionally one or more other pharmarceutically acceptable additives.
  • a pharmaceutically acceptable diluent and/or carrier optionally one or more other pharmarceutically acceptable additives.
  • compositions suitable for administration to subjects, such as human subjects, for example using the teaching a standard text such as Remington's Pharmaceutical Sciences, 18th ed, (Mack Publishing Company: Easton, Pa., 1990), pp. 1635-36), and by taking into account the selected route of delivery.
  • diluents and/or carriers and/or other additives that may be included in the compostions of the invention include, but are not limited to, water, glycols, oils, alcohols, aqueous solvents, organic solvents, DMSO, saline solutions, physiological buffer solutions, peptide carriers, starches, sugars, preservatives, antioxidants, coloring agents, pH buffering agents, granulating agents, lubricants, binders, disintegrating agents, emulsifiers, binders, excipients, extenders, glidants, solubilizers, stabilizers, surface active agents, suspending agents, tonicity agents, viscosity-altering agents, carboxymethyl cellulose, crystalline cellulose, glycerin, gum arabic, lactose, magnesium stearate, methyl cellulose, powders, saline, sodium alginate.
  • diluents and/or carriers and/or other additives used can be varied taking into account the nature of the active agents used (for example the solubility and stability of the active agents), the route of delivery (e.g. oral, parenteral, etc.), whether the agents are to be delivered over an extended period (such as from a controlled- release capsule), whether the agents are to be co-administered with other agents, and various other factors.
  • the route of delivery e.g. oral, parenteral, etc.
  • an extended period such as from a controlled- release capsule
  • agents are to be co-administered with other agents
  • the compounds of Formula I, I-a', I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-i, I-j, I-k, 1-1, 1-m, I-n, I-o, I-p, I-a-1, 1-b-1, 1-c-1, 1-d-1, I-e-1, I-f-1, 1-g-1, I-h- 1 , I-i- 1 , or Formula II, may be administered to the subject (or contacted with cells of the subject) in an amount effective to treat and/or prevent sarcopenia, and/or in an amount effective to reduce calcium "leak" through the RyR, and/or in an amount effective to reduce the calcium current through the RyR, and/or in an amount effective to stabilize gating of the RyR, and/or in amount effective to increase the binding of calstabin to the RyR complex in the subject, and/or in amount effective to reverse a malfunction
  • an effective amount of the agents of the invention to be administered to a subject taking into account whether the agent is being used prophylactically or therapeutically, and taking into account other factors such as the age, weight and sex of the subject, any other drugs that the subject may be taking, any allergies or contraindications that the subject may have, and the like.
  • an effective amount can be determined by the skilled artisan using known procedures, including analysis of titration curves established in vitro or in vivo.
  • the desired subject is a human
  • one of skill in the art can determine the effective dose from performing pilot experiments in suitable animal model species and scaling the doses up or down depending on the subjects weight etc.
  • Effective amounts can also be determined by performing clinical trials in individuals of the same species as the subject, for example starting at a low dose and gradually increasing the dose and monitoring the effects on sarcopenia.
  • Appropriate dosing regimens can also be determined by one of skill in the art without undue experimentation, in order to determine, for example, whether to administer the agent in one single dose or in multiple doses, and in the case of multiple doses, to determine an effective interval between doses.
  • an effective amount of the compounds of the invention to administer to a subject ranges from about 0.01 mg/kg/day to about 20 mg/kg/day, and/or is an amount sufficient to achieve plasma levels ranging from about 300 ng/ml to about 1000 ng/ml.
  • the amount of compounds from the invention ranges from about 5 mg/kg/day to about 20 mg/kg/day.
  • from about 10 mg/kg/day to about 20 mg/kg/day is administered.
  • from about 0.01 mg/kg/day to about 10 mg/kg/day is administered.
  • from about 0.01 mg/kg/day to about 5 mg/kg/day is administered.
  • from about 0.05 mg/kg/day to about 5 mg/kg/day is administered.
  • from about 0.05 mg/kg/day to about 1 mg/kg/day is administered.
  • compositions described herein may be administered to a subject by any suitable method that allows the agent to exert its effect on the subject in vivo.
  • the compositions may be administered to the subject by known procedures including, but not limitated to, by oral administration, sublingual or buccal administration, parenteral
  • the compounds of the invention may be administered parenterally, or by epifascial, intracapsular, intracutaneous, subcutaneous, intradermal, intrathecal, intramuscular, intraperitoneal, intrasternal, intravascular, intravenous, parenchymatous, or sublingual delivery. Delivery may be by injection, infusion, catheter delivery, or some other means, such as by tablet or spray.
  • the agent is adiminstered to the subject by way of delivery directly to the heart tissue, such as by way of a catheter inserted into, or in the proximity of the subject's heart, or by using delivery vehicles capable of targeting the drug to the heart.
  • the compounds of the invention may be conjugated to or administered in conjunction with an agent that is targeted to the heart, such as an antibody or antibody fragment.
  • a formulation of the compounds of the invention may be presented as capsules, tablets, powders, granules, or as a suspension or solution.
  • the formulation may contain conventional additives, such as lactose, mannitol, cornstarch or potato starch, binders, crystalline cellulose, cellulose derivatives, acacia, cornstarch, gelatins, disintegrators, potato starch, sodium carboxymethylcellulose, dibasic calcium phosphate, anhydrous or sodium starch glycolate, lubricants, and/or or magnesium stearate.
  • the compounds of the invention may be combined with a sterile aqueous solution that is isotonic with the blood of the subject.
  • a sterile aqueous solution that is isotonic with the blood of the subject.
  • Such a formulation may be prepared by dissolving the active ingredient in water containing physiologically-compatible substances, such as sodium chloride, glycine and the like, and having a buffered pH compatible with physiological conditions, so as to produce an aqueous solution, then rendering the solution sterile.
  • the formulation may be presented in unit or multi-dose containers, such as sealed ampoules or vials.
  • the formulation may be delivered by injection, infusion, or other means known in the art.
  • the compounds of the invention may be combined with skin penetration enhancers, such as propylene glycol, polyethylene glycol, isopropanol, ethanol, oleic acid, N-methylpyrrolidone and the like, which increase the permeability of the skin to the compounds of the invention and permit the compounds to penetrate through the skin and into the bloodstream.
  • skin penetration enhancers such as propylene glycol, polyethylene glycol, isopropanol, ethanol, oleic acid, N-methylpyrrolidone and the like, which increase the permeability of the skin to the compounds of the invention and permit the compounds to penetrate through the skin and into the bloodstream.
  • agents of the invention and the other agents useful for the treatment and/or prevention of sarcopenia may be administered to the subject at the same time, or at different times.
  • the agents of the invention and the other agents may be administered within minutes, hours, days, weeks, or months of each other, for example as part of the overall treatment regimen of a subject.
  • Agents of the invention useful for treating and/or preventing sarcopenia may be used in combination with the other agents that include, but are not limited to, ⁇ -adrenergic blockers, calcium channel blockers and anti-arrhythmic drugs.
  • the present invention is directed to methods for identifying additional compounds that may be useful for the treatment and/or prevention of sarcopenia.
  • Such methods may be based on, inter alia, identifying compounds that increase binding of calstabins to RyRs, and/or decrease the calcium current through RyR, and the like. Examples of suitable assays and screening methods that may be used to identify new compounds that may be useful for the treatment and/or prevention of sarcopenia are described in U.S.
  • the present invention encompasses compounds useful for the treatment and/or prevention of sarcopenia, and methods of treatment and/or prevention comprising
  • the compounds of the invention decrease the open probability of RyR, particularly protein kinase A (PKA) phosphorylated, and/or nitrosylated, and/or oxidized RyRs, and thereby decrease the Ca 2+ current through such channels under resting conditions when muscles are relaxed.
  • PKA protein kinase A
  • the compounds of the invention exert this effect, at least in part, by increasing the affinity with which calstabin proteins bind to RyRs, and/or by inhibiting a decrease in binding of calstabins to RyRs, and/or by inhibiting dissociation of calstabins from RyRs, particularly PKA phosphorylated RyRs.
  • the compounds of the invention decrease the open probability of RyR and decrease the "leak" of Ca 2+ through such channels by stabilizing the closed state of the channel without blocking the channel pore.
  • the present invention relates to use of benzothiazepine, benzoxazepine,
  • the present invention provides benzothiazepine, benzoxazepine, benzodiazepine and benzazepine compounds as described by the chemical formulae Formula I, I-a', I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-i, I-j, I-k, 1-1, 1-m, I-n, I-o, I-p, I-a-1, 1-b-1, 1-c-1, I-d-1, 1-e-1, I-f- 1 , 1-g-1, 1-h-1, 1-i-1, or Formula II, as described below.
  • the present invention provides methods for the treatment and/or prevention of sarcopenia that comprise administering compounds of Formula I to subjects in need thereof.
  • the present invention provides compositions useful for the treatment and/or prevention of sarcopenia that comprise compounds of Formula I.
  • the structure of Formula I is as follows:
  • n 0, 1, or 2;
  • q 0, 1, 2, 3, or 4;
  • Ri is selected from the group consisting of H, oxo, alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, heteroaryl, and heterocyclyl; wherein each alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, heteroaryl, and heterocyclyl may be optionally substituted;
  • R4 is selected from the group consisting of H, alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, heteroaryl, and heterocyclyl; wherein each alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, heteroaryl, and heterocyclyl may be optionally substituted;
  • Re is selected from the group consisting of -OR15, -NHNR15R16, -NHOH, -NR15R16, -CH 2 X, acyl, alkenyl, alkyl, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, and heterocyclylalkyl; wherein each acyl, alkenyl, alkyl, aryl, alkylaryl, cycloalkyl,
  • cycloalkylalkyl, heteroaryl, heterocyclyl, and heterocyclylalkyl may be optionally substituted
  • R 11 , Ri 2 , Ri 3 , and Ri 4 independently are selected from the group consisting of H, OH, NH 2 , -NHNH 2 , -NHOH, acyl, alkenyl, alkoxyl, alkyl, alkylamino, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, and heterocyclylalkyl; wherein each acyl, alkenyl, alkoxyl, alkyl, alkylamino, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl,
  • X is selected from the group consisting of halogen, -CN, -C0 2 Ri 5 , -NR15R16,
  • the nitrogen in the benzothiazepine ring may optionally be a quaternary nitrogen; and enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, hydrates, solvates, complexes, and prodrugs thereof.
  • Examples of compounds that may be used in conjunction with the invention include, without limitation, SI, S2, S3, S4, S5, S6, S7, S9, SI 1, S12, SI 3, S14, SI 9, S20, S22, S23, S24, S25, S26, S27, S36, S37, S38, S40, S43, S44, S45, S46, S47, S48, S49, S50, S51, S52, S53, S54, S55, S56, S57, S58, S59, S60, S61, S62, S63, S64, S66, S67, S68, S69, S70, S71, S72, S73, S74, S75, S76, S77, S78, S79, S80, S81, S82, S83, S84, S85, S86, S87, S88, S89, S90, S91, S92, S93, S94, S95, S96, S97, S98, S99, S100, S101,
  • the present invention provides methods and uses which comprise administering compounds of Formula I-a':
  • n 0, 1, or 2;
  • q 0, 1, 2, 3, or 4;
  • R 7 is selected from the group consisting of H, -OR15, -NR 15 R 16 , -NHNR15R16, -NHOH, -CH 2 X, alkyl, akenyl, alkynyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and
  • heterocyclylalkyl wherein each alkyl, akenyl, alkynyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl may be substituted or unsubstituted;
  • Rg and R9 independently are selected from the group consisting of -OH, acyl, alkenyl, alkoxyl, alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl;
  • each acyl, alkenyl, alkoxyl, alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl may be substituted or unsubstituted;
  • R 11 , R 12 , Ri 3 , and Ri 4 independently are selected from the group consisting of H, OH, NH 2 , -NHNH 2 , -NHOH, acyl, alkenyl, alkoxyl, alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; wherein each acyl, alkenyl, alkoxyl, alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl may be substituted or unsubstituted;
  • X is selected from the group consisting of halogen, -CN, -CO2R15, -NR15R16,
  • Ri 5 and Ri 6 independently are selected from the group consisting of H, acyl, alkenyl, alkoxyl, OH, NH 2 , alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and
  • heterocyclylalkyl wherein each acyl, alkenyl, alkoxyl, alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl may be substituted or unsubstituted; and optionally R15 and R1 ⁇ 2 together with the N to which they are bonded may form a heterocycle which may be substituted or unsubstituted;
  • the nitrogen in the benzothiazepine ring may be optionally a quaternary nitrogen; and enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, hydrates, solvates, complexes, and prodrugs thereof.
  • the present invention provides methods and uses which comprise administering compounds of Formula I-a:
  • n 0, 1, or 2;
  • q 0, 1, 2, 3, or 4;
  • R 5 is selected from the group consisting of -NR15R16, -(CH 2 ) z NRi 5 Ri6, -NHNR15R16, -NHOH, -ORis, -CH 2 X, acyl, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; wherein each acyl, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl may be substituted or unsubstituted, and wherein z is 1, 2, 3, 4, 5, or 6;
  • Re is selected from the group consisting of -ORi 5 , -NHNRi 5 Ri 6 , -NHOH, -NRi 5 Ri 6 , -CH 2 X, acyl, alkenyl, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; wherein each acyl, alkenyl, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl may be substituted or unsubstituted;
  • R 7 is selected from the group consisting of H, -OR i5 , -NRi 5 Ri 6 , -NHNRi 5 Ri 6 , -NHOH, -CH 2 X, alkyl, akenyl, alkynyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; wherein each alkyl, akenyl, alkynyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl may be substituted or unsubstituted;
  • Rg and R9 independently are selected from the group consisting of -OH, acyl, alkenyl, alkoxyl, alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl;
  • R 11 , R 12 , Ri 3 , and R 14 independently are selected from the group consisting of H, OH, NH 2 , -NHNH 2 , -NHOH, acyl, alkenyl, alkoxyl, alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; wherein each acyl, alkenyl, alkoxyl, alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl may be substituted or unsubstituted;
  • Ri 5 and Ri 6 independently are selected from the group consisting of H, acyl, alkenyl, alkoxyl, OH, NH 2 , alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and
  • heterocyclylalkyl wherein each acyl, alkenyl, alkoxyl, alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl may be substituted or unsubstituted; and optionally R 15 and R1 ⁇ 2 together with the N to which they are bonded may form a heterocycle which may be substituted or unsubstituted;
  • the nitrogen in the benzothiazepine ring may be optionally a quaternary nitrogen; and enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, hydrates, solvates, complexes, and prodrugs thereof.
  • n 0, 1, or 2.
  • the present invention provides methods and uses which comprise administering com ounds of formula I-b:
  • R 2 and n are as defined in compounds of formula I-a above;
  • R is H or OMe
  • R" is H.
  • the present invention provides methods and uses which comprise administering compounds formula of I-c:
  • each R, R 7 , q, and n is as defined in compounds of formula I-a above;
  • n 0, 1, or 2.
  • the present invention provides methods and uses which comprise administering compounds of formula I-c, wherein R 7 is selected from the group consisting of -OH, -NR15R16, alkyl, alkenyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; wherein each alkyl, akenyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl may be substituted or unsubstituted.
  • the present invention provides methods and uses which comprise administering com ounds of formula of I-d:
  • R and R" are independently selected from the group consisting of H, halogen, -OH,
  • acyl alkyl, alkoxyl, alkylamino, alkylthio, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-)aryl, (hetero-)arylthio, and (hetero-)arylamino; and wherein each acyl, alkyl, alkoxyl, alkylamino, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-)aryl, (hetero-)arylthio may be substituted or unsubsti
  • R 7 and n are as defined in compounds of formula I-a above; and enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, hydrates, solvates, complexes and pro-drugs thereof.
  • R is H or OMe
  • R" is H.
  • the present invention provides methods and uses which comprise administering compounds of formula I-d, wherein Ry is selected from the group consisting of -OH, -NR 15 R 16 , alkyl, alkenyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; wherein each alkyl, akenyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl may be substituted or unsubstituted.
  • Ry is selected from the group consisting of -OH, -NR 15 R 16 , alkyl, alkenyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; wherein each alkyl, akenyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocycly
  • the present invention provides methods and uses which comprise administering compounds of formula of I-e:
  • each R, R 5 , q and n is as defined compounds of formula I-a above; and enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, hydrates, solvates, complexes and pro-drugs thereof.
  • n 0, 1 , or 2.
  • the present invention provides methods and uses which comprise administering compounds of formula I-e, wherein R 5 is selected from the group consisting of-NRi 5 Ri 6 , -(CH 2 ) z NRi 5 Ri 6 , -NHOH, -ORi 5 , -CH 2 X, alkyl, alkenyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; wherein each acyl, alkyl, alkenyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl may be substituted or unsubstituted.
  • the present invention provides methods and uses which comprise administering compounds of formula I-e, wherein R5 is an alkyl substituted by at least one labeling group, such as a fluorescent, a bioluminescent, a chemiluminescent, a colorimetric and a radioactive labeling group.
  • R5 is an alkyl substituted by at least one labeling group, such as a fluorescent, a bioluminescent, a chemiluminescent, a colorimetric and a radioactive labeling group.
  • a fluorescent labeling group can be selected from bodipy, dansyl, fluorescein, rhodamine, Texas red, cyanine dyes, pyrene, coumarins, Cascade BlueTM, Pacific Blue, Marina Blue, Oregon Green, 4',6-Diamidino-2-phenylindole (DAPI), indopyra dyes, lucifer yellow, propidium iodide, porphyrins, arginine, and variants and derivatives thereof.
  • the present invention provides methods and uses which comprise administering compounds of formula of I-f:
  • R and R" are independently selected from the group consisting of H, halogen, -OH,
  • acyl alkyl, alkoxyl, alkylamino, alkylthio, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-)aryl, (hetero-)arylthio, and (hetero-)arylamino; and wherein each acyl, alkyl, alkoxyl, alkylamino, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-)aryl, (hetero-)arylthio may be substituted or unsubsti
  • R 5 and n are as defined in compounds of formula I-a above; and enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, hydrates, solvates, complexes and pro-drugs thereof.
  • a preferred compound of formula I-f is S36, in particular in the form of a sodium salt.
  • the present invention provides methods and uses which comprise administering compounds of formula I-f, wherein -(CH 2 ) z NRi 5 Ri6, selected from the group consisting of-NRi 5 Ri 6 , -NHOH, -ORi 5 , -CH 2 X, alkyl, alkenyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; wherein each acyl, alkyl, alkenyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl may be substituted or unsubstituted.
  • the present invention provides methods and uses which comprise administerin mpounds of formula of I-g:
  • W is S or O; each R, Ri 5 , Ri 6 , q, and n is as defined in compounds of formula I-a above; and enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, hydrates, solvates, complexes and pro-drugs thereof.
  • the present invention provides methods and uses which comprise administering compounds of formula I-g, wherein Ri 5 and Ri 6 independently are selected from the group consisting of H, OH, NH 2 , alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; wherein each alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl may be substituted; and optionally R15 and R1 ⁇ 2 together with the N to which they are bonded may form a heterocycle which may be substituted.
  • Ri 5 and Ri 6 independently are selected from the group consisting of H, OH, NH 2 , alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; wherein each alkyl, alkyla
  • the present invention provides methods and uses which comprise administering compounds of formula I-g, wherein W is O or S.
  • the present invention provides methods and uses which comprise administerin compounds of formula of I-h:
  • W is S or O
  • R and R" are independently selected from the group consisting of H, halogen, -OH,
  • acyl alkyl, alkoxyl, alkylamino, alkylthio, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-)aryl, (hetero-)arylthio, and (hetero-)arylamino; and wherein each acyl, alkyl, alkoxyl, alkylamino, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-)aryl, (hetero-)arylthio may be substituted or unsubsti
  • Ri 5 , Ri 6 and n are as defined in compounds of formula I-a above;
  • R' is H or OMe
  • R" is H.
  • the present invention provides methods and uses which comprise administering compounds of formula I-h, wherein W is O or S.
  • R 17 is selected from the group consisting of -NR15R16, -NHNR15R16, -NHOH, -OR15, -CH 2 X, alkenyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl;
  • alkenyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl may be substituted or unsubstituted;
  • each R, q, and n is as defined in compounds of formula I-a above; and enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, hydrates, solvates, complexes and pro-drugs thereof.
  • n 0, 1, or 2.
  • the present invention provides methods and uses which comprise administering compounds of formula I-i, wherein Rn is -NRi 5 Ri 6 , and -ORi 5 .
  • R i7 is -OH, -OMe, -NEt, -NHEt, -NHPh, -NH 2 , or
  • the present invention provides methods and uses which comprise administering compounds of formula of I- :
  • R and R" are independently selected from the group consisting of H, halogen, -OH,
  • Ri 7 is selected from the group consisting of -NR15R16, -NHNR15R16, -NHOH, -OR15, -CH 2 X, alkenyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; wherein each alkenyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl may be substituted or unsubstituted;
  • n is as defined in compounds of formula I-a;
  • R' is H or OMe
  • R" is H.
  • the present invention provides methods and uses which comprise administering compounds of formula I-k:
  • R and R" are independently selected from the group consisting of H, halogen, -OH,
  • acyl alkyl, alkoxyl, alkylamino, alkylthio, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-)aryl, (hetero-)arylthio, and (hetero-)arylamino; and wherein each acyl, alkyl, alkoxyl, alkylamino, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-)aryl, (hetero-)arylthio may be substituted or unsubsti
  • Rig is selected from the group consisting of -NRi 5 Ri 6 , -OR 15 , alkyl, aryl, cycloalkyl, heterocyclyl, and at one labeling group; wherein each alkyl, aryl, cycloalkyl, and heterocyclyl may be substituted or unsubstituted;
  • p is any one of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, with each value of p representing a different embodiment; and n is 0, 1, or 2;
  • R is H, OMe, or C 2 -C 4 alkoxyl;
  • R" is H;
  • n is 0; and
  • Rig is Ci-C 4 alkyl.
  • n is 0, and Rig is C 1 -C4 alkyl, such as Me, Et, propyl, and butyl.
  • n 2
  • Ri 8 is pyrrolidine, piperidine, piperazine, or morpholine.
  • m is 3, 4, 5, 5, 7, or 8
  • Rig is a fluorescent labeling group selected from bodipy, dansyl, fluorescein, rhodamine, Texas red, cyanine dyes, pyrene, coumarins, Cascade BlueTM, Pacific Blue, Marina Blue, Oregon Green, 4',6-Diamidino-2-phenylindole (DAPI), indopyra dyes, lucifer yellow, propidium iodide, porphyrins, arginine, and variants and derivatives thereof.
  • the present invention provides methods and uses which comprise administering com ounds of formula of I-l:
  • R and R" are independently selected from the group consisting of H, halogen, -OH,
  • acyl alkyl, alkoxyl, alkylamino, alkylthio, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-)aryl, (hetero-)arylthio, and (hetero-)arylamino; and wherein each acyl, alkyl, alkoxyl, alkylamino, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-)aryl, (hetero-)arylthio may be substituted or unsubsti
  • Re and n are as defined in compounds of formula I-a; and enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, hydrates, solvates, complexes and pro-drugs thereof.
  • R' is H or OMe
  • R" is H.
  • the present invention provides methods and uses which comprise administering compounds of formula 1-1, wherein R ⁇ is selected from the group consisting of -NRi 5 Ri 6 , -NHNRi 5 Ri 6 , -ORi 5 , -NHOH, -CH 2 X, acyl, alkenyl, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; wherein each acyl, alkenyl, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl may be substituted or unsubstituted.
  • Re is -NR 15 R 16 such as -NHPh, pyrrolidine, piperidine, piperazine, morpholine, and the like.
  • R 6 is alkoxyl, such as -O-tBu.
  • the present invention provides methods and uses which comprise administering com ounds of formula I-m:
  • acyl alkyl, alkoxyl, alkylamino, alkylthio, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-)aryl, (hetero-)arylthio, and (hetero-)arylamino; and wherein each acyl, alkyl, alkoxyl, alkylamino, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-)aryl, (hetero-)arylthio may be substituted or unsubsti
  • Rg, R 9 and n are as defined in compounds of formula I-a above; and enantiomers,
  • R is H or OMe
  • R" is H.
  • the present invention provides methods and uses which comprise administering compounds of formula I-m, wherein Rg and R 9 are independently alkyl, aryl, -OH, alkoxyl, or alkylamino.
  • Rg is Ci-C 4 alkyl such as Me, Et, propyl and butyl; and R 9 is aryl such as phenyl.
  • the present invention provides methods and uses which comprise administering com ounds of formula I-n,
  • R d is CH 2 , or NR a ;
  • R a is H, -(Ci-C 6 alkyl)-aryl, wherein the aryl is a disubstituted phenyl or a
  • benzo[l,3]dioxo-5-yl group or an amine protecting group (e.g., a Boc group);
  • R b is hydrogen of alkoxy (e.g., methoxy).
  • Representative compounds of Formula I-n include without limitation S101, SI 02,
  • the invention provides compounds of Formula I-o:
  • Re is substituted or unsubstituted -Ci-C 6 alkyl, -(Ci-C 6 alkyl)-phenyl, or -(Ci-C 6 alkyl)-C(0)R b ;
  • R b is -OH or -0-(Ci-C 6 alkyl), and
  • phenyl or substituted alkyl is substituted with one or more of halogen, hydroxyl, -Ci-C 6 alkyl, -0-(Ci-C 6 alkyl), -NH 2 , -NH(Ci-C 6 alkyl), -N(Ci-C 6 alkyl) 2 , cyano, or dioxolane.
  • Representative compounds of Formula I-o include without limitation S 107, SI 10, Si l l, S120, and S121.
  • Rc is -(Ci-Ce alkyl)-NH 2 , -(Ci-C 6 alkyl)-OR f , wherein R f is H or -C(0)-(Ci-C 6 )alkyl, or -(Ci-C 6 alkyl)-NHR g wherein Rg is carboxybenzyl.
  • Representative compound of Formula I-p include without limitation SI 09, S122, and SI 23.
  • the compounds of Formula I, I-a', I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-i, I-j, I-k, 1-1, 1-m, I-n, I-o, I-p, and Formula II can be used in methods that treat and/or prevent sarcopenia, and may also be used in compositions suitable for the treatment and/or prevention of sarcopenia.
  • the compounds used have structures as described by Formula I-a, I-b, I-e, I-f, I-g, I-h, I-i, I-j, I-k, I-n, I-o, or I-p.
  • Another preferred embodiment relates to compounds of Formula I-a-1 :
  • n 0, 1, 2, 3, or 4;
  • R 2 and R 3 together with the nitrogen and carbon to which they are respectively attached, form an unsubstituted or substituted heterocycle other than a piperazine;
  • R 3 and R 4 together with the carbon atoms to which they are respectively attached, form an unsubstituted or substituted cycloalkyl or heterocyclic ring;
  • R4 is selected from the group consisting of R 5 and oxo;
  • each R 5 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, alkylaryl, and alkylheteroaryl;
  • Rg, R9, R 11 and R 12 are independently selected from the group consisting of R 5 , OR 5 , and -N(R 5 ) 2 ;
  • Z is a halogen selected from F, CI, Br and I;
  • Ri 3 and R 14 are independently selected from the group consisting of R 5 , or R 13 and R 14 together with the N to which they are bonded may form an unsubstituted or substituted heterocycle;
  • alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, alkylaryl, and alkylheteroaryl may be substituted or unsubstituted;
  • nitrogen in the benzoxazepine ring may optionally be a quaternary nitrogen
  • the invention further provides a number of more preferred structures that fall within the general structure of formula I-a-1.
  • Preferred compounds of the present invention include:
  • each R 5 is independently hydrogen, or an unsubstituted or substituted alkyl, alkylaryl, aryl, or heterocyclyl.
  • R is methoxy
  • n 1 or 2
  • n 1
  • More preferred compounds of (a) include Rg and R9 being independently OR 5 . Also in (a)-(d), more preferred compounds of (a)-(d) include each R 5 being independently hydrogen, or an unsubstituted or substituted alkyl, alkylaryl, aryl, or heterocyclyl.
  • each R is independently OR 5 at positions 7 and 8 of the benzoxazepine ring.
  • the more preferred compounds of the invention specifically include those of formula I-a-1, wherein:
  • n 1
  • R is OR 5 or OCZ 3 at position 7 of the benzoxazepine ring
  • Ri 3 and Ri 4 are either each H or are bonded to make , wherein Rj is CH 2 , NH,
  • Rj may optionally be a quaternary nitrogen; or R 2 and R 3 together with the nitrogen and carbon to which they are respectively attached, form an unsubstituted or substituted heterocycle other than a piperazine; or
  • n 2
  • each R is independently OR 5 at positions 7 and 8 of the benzoxazepine ring
  • N-benzo[l,3]dioxo-5-yl, or N-C( 0)OC(R 5 ) 3 , wherein the nitrogen in Rj may optionally be a quaternary nitrogen; or
  • n 1
  • R is OR 5 at position 6 of the benzoxazepine ring
  • R 2 and R 3 together with the nitrogen and carbon to which they are respectively attached, form an unsubstituted or substituted heterocycle other than a piperazine; or
  • R being OR 5 at position 7 of the benzoxazepine ring wherein each R 5 is independently hydrogen, or an unsubstituted or substituted alkyl, alkylaryl, aryl, or heterocyclyl.
  • Still other preferred compounds are those represented by the structure of any one or more of formula I-b-1, I-c-1, 1-d-1, 1-e-1, 1-f-1, 1-g-1, 1-h-1, and I-i- 1 , and their
  • R, n and R 2 are as in formula I-a-1 and Rd is CH 2 , NH, O,
  • N-benzo[l,3]dioxo-5-yl, or N-C( 0)OC(R 5 )3, wherein the nitrogen in Rj may optionally be a quaternary nitrogen.
  • the most preferred compounds of formula I-b-1 to I-i-1 include those where R is OR 5 at position 7 of the benzoxazepine ring wherein each R5 is independently hydrogen, or an unsubstituted or substituted alkyl, alkylaryl, aryl, or heterocyclyl.
  • R is methoxy at position 7 of the benzothiazepine ring.
  • Examples of compounds that may be used in conjunction with the invention include, without limitation, SI, S2, S3, S4, S5, S6, S7, S9, SI 1, S12, SI 3, S14, SI 9, S20, S22, S23, S24, S25, S26, S27, S36, S37, S38, S40, S43, S44, S45, S46, S47, S48, S49, S50, S51, S52, S53, S54, S55, S56, S57, S58, S59, S60, S61, S62, S63, S64, S66, S67, S68, S69, S70, S71, S72, S73, S74, S75, S76, S77, S78, S79, S80, S81, S82, S83, S84, S85, S86, S87, S88, S89, S90, S91, S92, S93, S94, S95, S96, S97, S98, S99, S100, S101,
  • each R is independently selected from the group consisting of H, halogen, -OH, -NH 2 , -N0 2 , -CN, -N 3 , -S0 3 H, acyl, alkyl, alkylamino, cycloalkyl, heterocyclyl, heterocyclylalkyl, alkenyl, (hetero-)aryl, (hetero-)arylthio, and (hetero-) arylamino; wherein each acyl, alkyl, alkoxyl, alkylamino, cycloalkyl, heterocyclyl, heterocyclylalkyl, alkenyl, (hetero-)aryl, (hetero-)arylthio, and (hetero-)arylamino may be substituted with one or more radicals independently selected from the group consisting of hal
  • each R is independently selected from the group consisting of H, halogen, -OH, -NH 2 , -N0 2 , -CN, -N 3 , -S0 3 H, acyl, alkyl, alkylamino, cycloalkyl, heterocyclyl, heterocyclylalkyl, alkenyl, (hetero-)aryl, (hetero-)arylthio, and (hetero-)arylamino; wherein each acyl, alkyl, alkoxyl, alkylamino, cycloalkyl, heterocyclyl, heterocyclylalkyl, alkenyl, (hetero-)aryl,
  • (hetero-)arylthio, and (hetero-)arylamino may be substituted with one or more radicals independently selected from the group consisting of halogen, N, O, -S-, -CN, -N 3 , -SH, nitro, oxo, acyl, alkyl, alkoxyl, alkylamino, alkenyl, aryl, (hetero-)cycloalkyl, and (hetero-)cyclyl.
  • R 5 is selected from the group consisting of -NR 16 , -(CH 2 ) z NRi 5 Ri6, NHNHRie, NHOH, -ORis, CONH 2 NHRi 6 , CONRie, CH 2 X, acyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; wherein each acyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl may be substituted with one or more radicals
  • the present invention provides use of the compounds of Formula II in the method of the invention.
  • Formula II is
  • Formula II is discussed also in co-pending application 10/680,988, the disclosure of which is incorporated herein in its entirety by reference.
  • the -S- or -O- of the ring in all embodiments disclosed herein can instead be replaced by -CH 2 - or by -NH- with such compounds being expected to be useful by reducing calcium "leak” or calcium current through the RyR, stabilizing gating of the RyR, or increasing the binding of calstabin to the RyR complex in the subject.
  • the compounds of the invention are useful for the treatment and/or prevention of disorders and conditions associated with abnormal function of RyR receptors, particularly RyRl and RyR2 (with the ryanodine receptor 2 found predominantly in the heart), where such disorders and conditions are characterized by an increase in the open probability of, and in increase in the calcium current through, RyRs.
  • protein is isolated and purified from cells of a subject using standard methods known in the art, including, without limitation, extraction from the cells (e.g., with a detergent that solubilizes the protein) where necessary, followed by affinity purification on a column, chromatography (e.g., FTLC and HPLC), immunoprecipitation (with an antibody), and precipitation (e.g., with isopropanol and a reagent such as Trizol). Isolation and purification of the protein is followed by electrophoresis (e.g., on an SDS- polyacrylamide gel).
  • phosphorylated RyR to associate physically with calstabin (e.g. , binding of approximately two fold or, approximately five fold, above the background binding of a negative control) in cells of the subject and enhancing, increasing or improving the ability of calstabin to associate physically with phosphorylated RyR (e.g., binding of approximately two fold, or,
  • a decrease in the level of RyR-bound calstabin in cells of a subject is limited or prevented by directly decreasing the level of phosphorylated RyR in cells of the subject or by indirectly decreasing the level of phosphorylated RyR in the cells (e.g., by targeting an enzyme (such as PKA) or another endogenous molecule that regulates or modulates the functions or levels of phosphorylated RyR in the cells).
  • the level of phosphorylated RyR in the cells is decreased by at least 10% in the method of the present invention. In another embodiment, the level of phosphorylated RyR is decreased by at least 20%.
  • the compounds of the present invention may be synthesized as described in published PCT application WO 07/024717 and U.S. patent application 1 1/506,285, the entire contents of which are hereby incorporated by reference.
  • the present invention provides use of compounds of the following formula for preparing many of the compounds disclosed herein:
  • a PCR fragment carrying the point mutation (RyRl-2844 S > D) was used to replace the WT sequence by conventional cloning methods (Fig. 14).
  • the targeting vector was electroporated into ES cells derived from hybrid C57BL/6N x 129SvEv mice (Taconic), which, after selection, were implanted into blastocysts in C57BL/6N mice. Chimeras were crossed with C57BL/6N to generate the Fl . After confirmation of germ line transmission and crossing with Ella ere mice to excise the neomycin cassette, mice were backcrossed for more than six generations into the C57BL/6J strain. ES cell preparation and implantation were performed at inGenious Targeting Laboratory.
  • FDB fibers were obtained by enzymatic dissociation as previously described (Aydin et al., 2009). FDB muscles from both hind limbs were incubated for -2 hours at 37°C in -4 ml Dulbecco's Modified Eagles Medium (DMEM) containing 0.3% collagenase 1 (Sigma) and 10% fetal bovine serum. The muscles were transferred to a culture dish containing fresh DMEM ( ⁇ 4 ml) and gently triturated using a 1000 ⁇ pipette until the muscles were dissociated. The cell suspension was stored in an incubator at 37°C/5% C0 2 until the start of the experiment.
  • DMEM Dulbecco's Modified Eagles Medium
  • FDB fibers were loaded with the fluorescent Ca 2+ indicator Fluo-4 AM (5 ⁇ , Invitrogen/Molecular probes) for 15 min in room temperature (RT).
  • the cells were allowed to attach to a laminin coated glass cover slip that formed the bottom of a perfusion chamber.
  • the cells were then superfused with tyrode solution (in mM: NaCl 121, KC1 5.0, CaCl 2 1.8, MgCl 2 0.5, NaH 2 P0 4 0.4, NaHC0 3 24, EDTA 0.1, glucose 5.5; bubbled with 0 2 /C0 2
  • the fibers were triggered to tetanic contraction using electrical field stimulation (pulses of 0.5 ms at 70 Hz for a duration of 350 ms, at supra-threshold voltage) and Fluo-4 fluorescence was monitored using a confocal microscope system (Zeiss LSM 5 Live, 40x oil immersion lens, excitation wavelength was 488 nm and the emitted fluorescence was recorded between 495-525 nm).
  • the use of the single excitation/emission dye fluo-4 necessitates normalizing to prestimulation values to negate possible differences in dye loading and excitation strength.
  • mice were euthanized and EDL muscles were dissected and stored in a HEPES-buffered physiological medium (in mM: 119 NaCl, 5 KC1, 1.25 CaCl 2 , 1 MgS0 4 , 10 glucose, 1.1 mannitol, 10 HEPES, pH 7.4). Muscles were then rapidly placed in a dissecting chamber and the solution exchanged with a relaxing solution (in mM: 140 K-glutamate, 10 HEPES, 10 MgCl 2 , 0.1 EGTA, pH 7.0).
  • a relaxing solution in mM: 140 K-glutamate, 10 HEPES, 10 MgCl 2 , 0.1 EGTA, pH 7.0.
  • Bundles of 5 to 10 EDL fibers were manually dissected, mounted as described previously (Lacampagne et al, 1998) and permeabilized in a relaxing solution containing 0.01% saponin for 30 s. After washing with saponin free solution, the solution was changed to an internal medium (in mM: 140 K- glutamate, 5 Na 2 ATP, 10 glucose, 10 HEPES, 4.4 MgCl 2 , 1.1 EGTA, 0.3 CaCl 2 , Fluo-3 0.05 (pentapotassium salt, Invitrogen, USA), pH 7.0) for Ca 2+ sparks acquisition as previously reported (Bellinger et al, 2009; Reiken et al, 2003; Ward et al, 2003).
  • an internal medium in mM: 140 K- glutamate, 5 Na 2 ATP, 10 glucose, 10 HEPES, 4.4 MgCl 2 , 1.1 EGTA, 0.3 CaCl 2 , Fluo-3 0.05 (pentapotassium salt, In
  • the mean F value for the image was calculated by summing and averaging the temporal F at each spatial location while ignoring potential spark areas. This F value was then used to create a AF/F image pixel by pixel. Statistical comparisons were performed using the ANOVA test with a significance level set at ⁇ 0.05. The investigators were blinded to the genotype, age and treatment of subjects.
  • Muscle tissue from the young, aged and SI 07 groups was homogenized using a tissue miser (Fisher Scientific) at the highest speed for 1 min with 2 volumes of: 20 mM Tris- maleate (pH 7.4), 1 mM EDTA and protease inhibitors (Roche). Homogenate was centrifuged at 4,000 g for 15 min at 4°C and the following supernatant was centrifuged at 40,000 g for 30 min at 4°C. The final pellet, containing the SR fractions, was resuspended and aliquoted using the following solution: 250 mM sucrose, 10 mM MOPS (pH 7.4), 1 mM EDTA and protease inhibitors. Samples were frozen in liquid nitrogen and stored at -80°C.
  • SR vesicles containing RyRl were fused to planar lipid bilayers formed by painting a lipid mixture of phosphatidylethanolamine, phosphatidylcholine and phosphatidylserine (Avanti Polar Lipids) in a 5:3:2 ratio across a 200- ⁇ hole in polysulfonate cups (Warner Instruments) separating 2 chambers.
  • the final concentration of lipids was 40 mg/ml dissolved in decane.
  • Membrane thinning was assayed by applying a triangular wave test pulse. Typical capacitance values were 100-250 pF.
  • SR vesicles were added to the cis side and fusion with the lipid bilayer was induced by making the cis side hyperosmotic by the addition of 400-500 mM KC1. After the appearance of potassium and chloride channels, the cis side was perfused with the cis solution.
  • Single-channel currents were recorded at 0 mV using a Bilayer Clamp BC-525C amplifier (Warner Instruments), and filtered with a low-pass Bessel filter eight pole (Warner Instruments) at 1 kHz and then sampled at 4 kHz. Data acquisition was performed by using Digidata 1322A and Axoscope 10 software (Axon Instruments).
  • EDL muscles were dissected from the hind limbs using micro dissection scissors and forceps. Stainless steel hooks were tied to the tendons of the muscles using nylon sutures. The muscle was thereafter mounted between a force transducer (Harvard apparatus) and an adjustable hook. The muscle preparation was immersed in a stimulation chamber containing 0 2 /C0 2 (95/5%) bubbled Tyrode solution (in mM: NaCl 121, KC1 5.0, CaCl 2 1.8, MgCl 2 0.5, NaH 2 P0 4 0.4, NaHC0 3 24, EDTA 0.1, glucose 5.5). The muscle was stimulated to contraction via application of an electrical field between two platinum electrodes (Aurora Scientific) attached to the stimulation chamber. The control unit for the electrical field stimulation as well as the data acquisition system came from Aurora Scientific (Ontario, Canada).
  • the muscle length was adjusted to the length (L 0 ) that yielded the maximum force.
  • the force-frequency relationships were then determined by triggering contraction using incremental stimulation frequencies (EDL: 0.5 ms pulses at 2-150 Hz for 350 ms at supra-threshold voltage). Between each stimulation, the muscle was allowed to rest for ⁇ 1 minute. At the end of the force measurement, the length (L 0 ) and weight of the muscle was measured, where after the muscle was snap frozen in liquid N 2 .
  • the absolute force was normalized to the muscle cross-sectional area, calculated as the muscle weight divided by the length and a muscle density constant of 1.056 kg/m 3 (Yamada et al, 2009). RyRl immunoprecipitation and immunoblotting
  • EDLs were isotonically lysed in 0.5 ml of a buffer containing 50 mM Tris-HCl (pH 7.4), 150 mM NaCl, 20 mM NaF, 1.0 mM Na 3 V0 4 , and protease inhibitors.
  • An anti-RyR antibody (4 ⁇ g 5029 Ab) was used to immunoprecipitate RyRl from 250 ⁇ g of tissue homogenate.
  • the samples were incubated with the antibody in 0.5 ml of a modified RIPA buffer (50 mM Tris-HCl pH 7.4, 0.9% NaCl, 5.0 mM NaF, 1.0 mM Na 3 V0 4 , 1% Triton- XI 00, and protease inhibitors) for 1 hr at 4°C.
  • the immune complexes were incubated with protein A Sepharose beads (Sigma, St. Louis, MS) at 4°C for 1 hr and the beads were washed three times with buffer.
  • DNP-hydrazone 2,4- dinitrophenylhydrazone
  • DNPH 2,4- dinitrophenylhydrazine
  • skeletal SR membranes (100 ⁇ g) were resuspended in 200 ⁇ of buffer (10 mM Tris-HCl, pH 7.2 with complete protease inhibitors (Roche Applied Science)). The samples were treated with 1 mM H 2 0 2 and/or 100 ⁇ ⁇ 2 (l-Hudroxy-2-oxo-[N-ethyl-2-aminoethyl]-3-ethyl-l-triazen; A.G. Scientific, USA) for 30 min at room temperature. After the reaction is completed, RyRl was immunoprecipitated from the sample with an RyR antibody and the immunoprecipitates were analyzed for total RyRl, oxidized RyRl, and calstabinl associated with the channel complex as described.
  • buffer 10 mM Tris-HCl, pH 7.2 with complete protease inhibitors (Roche Applied Science)
  • the samples were treated with 1 mM H 2 0 2 and/or 100 ⁇ ⁇ 2 (l-
  • Fluorescence changes in mitochondria-rich regions was followed over time and quantification was made using ImageJ. In each cell, at each time point, three different mitochondrial-rich regions were analyzed and averaged. Fluorescence measurements were normalized to the baseline fluorescence (F 0 ) in the same cell at the start of the experiment. Statistical significance was tested using analysis of variance (two-way repeated measures ANOVA).
  • Enzymatically dissociated FDB fibers were incubated with the fluorescent indicator Rhod-2/ AM (Invitrogen by Life Technologies/Molecular Probes, USA; 5 ⁇ ) for ⁇ 1 hour at room temperature.
  • Rhod-2 was taken up in the mitochondria
  • cell were simultaneously loaded with the fluorescent indicator Mitotracker green (Fig. 11); Invitrogen by Life Technologies/Molecular Probes, USA; 0.2 ⁇ ; 30 min room temperature).
  • Mitotracker green Fig. 11
  • Invitrogen by Life Technologies/Molecular Probes, USA 0.2 ⁇ ; 30 min room temperature.
  • the mitochondria are lined up along the sides of the z-lines. When Rhod-2 and Mitotracker Green are loaded into the mitochondria, a striated pattern of fluorescence is shown (Aydin et al, 2009; Lannergren et al, 2001).
  • Rhod-2 fluorescence was measured using a confocal microscope (Zeiss LSM 5 Live, 40x oil immersion lens) with excitation at 532 nm and the emitted signal collected through a band pass filter (540-625 nm). Mitotracker green was excited at 488 nm and the emitted fluorescence collected at >510 nm. ImageJ was used to quantify changes in Rhod-2 fluorescence in mitochondria rich areas (confirmed by overlapping Rhod-2 and mitotracker green signals). Statistical significance was tested using analysis of variance (ANOVA). Reactive nitrogen species (RNS) detection
  • the EDL samples were fixed with formalin, embedded in paraffin wax, and sliced at 5-um thickness.
  • the sections were deparaffinized, stained with hematoxylin and eosin (HE staining, Sigma- Aldrich Co., St. Louis, MO) and observed using light microscopy.
  • the images were captured using a SPOT RT slider camera (Diagnostic Instruments Inc., Sterling Heights, MI) and analyzed with ImageJ.
  • EDL muscles were fixed in 2.5% glutaraldehyde in 0.1M Sorenson's buffer (PH 7.2) followed by one hour of postfixing with 1% Os0 4 in Sorenson's buffer. After dehydration the tissue samples were embedded in Lx-112 (Ladd Research Industries) and 60 nm sections were cut using an ultramicrotome (MT-7000). The sections were then stained with uranyl acetate and lead citrate and examined under an electron microscope (JEM- 1200 EXII, JEOL) and images were taken using an ORCA-HR digital camera (Hamamatsu) and recorded with an AMT Image Capture Engine. Statistics
  • embodiment G are shown immunoblots of immunoprecipitated RyRl from young and aged mice.
  • DNP 2,4-dinitrophenylhydrazone.
  • P*RyRl Phosphorylated RyRl (at serine 2844). See also Figures 8 and 2A.
  • the dashed line indicates application of Antimycin A (10 ⁇ ) as a positive control for superoxide production.
  • * P ⁇ 0.05 indicates significant difference between the control rapamycin group and no rapamycin or SI 07 groups (ANOVA).
  • In embodiment D are shown the effect of rapamycin-induced Ca 2+ leak on RNS production in FDB fibers measured with the RNS indicator DAF. Arrow indicates application of rapamycin.
  • the NO donor S-nitroso-N-acetylpenicillamine (SNAP; 100 nM) was applied as a positive control at the end of each experiment (indicated by dashed line).
  • a and B are shown representative Ca 2+ transients Fluo-4 fluorescence in FDB muscle fibers during a 70Hz tetanic stimulation in mice that did not receive (A) or received SI 07 in the drinking water (B).
  • D are shown are representative single channel current traces of skeletal RyRl channels isolated from young, aged, and aged + SI 07 treated mice.
  • Figures 5A and B show elevated Ca 2+ spark frequency is reversed by SI 07 in EDL muscle from aged WT mice and RyRl-S2844D mice but not in calstabinl KO mice.
  • embodiment A are shown line scans of Fluo-4 fluorescence from permeablized EDL muscle fibers (young: upper panel; aged: middle panel; aged +S107: lower panel) showing Ca 2+ spark activity.
  • the heat diagram indicates the normalized change in fluorescence intensity (AF/F0).
  • Figures 6A-H show that improved muscle function and exercise capacity following SI 07 treatment of aged mice requires calstabinl .
  • embodiment A are shown immunoblot of immunoprecipitated RyRl from WT, 1 month old (1 m), 6 month old (6 m) RyRl-S2844D mice and 6 month old (6 m) RyRl-S2844D mice that was treated with SI 07.
  • RyRl from RyRl- S2844D mice are progressively oxidized (DNP) and depleted of calstabinl with age.
  • embodiment C are shown EDL muscle force-frequency curves in 6 month old RyRl-S2844D mice and young WT mice (from the same animals as in embodiment A).
  • SI 07 treatment (4 weeks) significantly increased muscle force in the RyRl-S2844D mice (mean ⁇ SEM).
  • embodiment D are shown peak Ca 2+ transient amplitudes at 70 Hz tetanic stimulation [peak Fluo-4 fluorescence (F) was normalized to resting fluorescence (F0), AF/F0].
  • embodiment E are shown EDL muscle from muscle-specific calstabinl KO mice produce significantly less force compared to young WT.
  • SI 07 treatment (4 weeks) did not restore EDL muscle force in muscle-specific calstabinl KO mice.
  • In embodiment F are shown daily voluntary running distance in young WT mice with or without SI 07 treatment and in muscle-specific calstabinl KO mice with or without SI 07 treatment (mean, ⁇ SEM; * P ⁇ 0.05 (ANOVA). The arrow indicates start of the SI 07 treatment.
  • In embodiment G are shown immunoblot of immunoprecipitated muscle RyRl from young WT, aged (18 month) WT, young transgenic mice with mitochondrial targeted overexpression of catalase (MCAT) and aged (18 month) MCAT mice.
  • MCAT catalase
  • FIGS 7A-E show model of RyRl -mediated SR Ca 2+ leak and mitochondrial dysfunction in aging skeletal muscle.
  • SR sarcoplasmic reticulum
  • ROS reactive oxygen species
  • embodiment B are shown DCF fluorescence when normalized to the fluorescence at 10 min in presence of H 2 0 2 (100 ⁇ ).
  • Figures show mean ⁇ SEM, statistical significance for both panels were obtained by an ANOVA (* P ⁇ 0.05, ** P ⁇ 0.01, *** P ⁇ 0.001).
  • FIGS 9A-F show RyRl from aged rat skeletal muscle are cysteine-nitrosylated, oxidized and depleted of calstabinl .
  • embodiment A are shown immunoblots of
  • E and F are shown in vitro oxidation (H 2 0 2 ) and nitrosylation (using the NO donor Noc-12) of skeletal muscle SR microsomes leads to calstabinl depletion.
  • Figures 10A-E show electron microscopy of EDL muscle.
  • A are shown representative image depicting morphologically normal mitochondria in EDL muscle from a young WT mouse.
  • B-D are shown representative images of EDL muscle from aged (B), RyRl-2844D (C), and calstabinl deficient (D) mice.
  • E are shown fraction of mitochondria with abnormal morphology (for each group, the number of normal and abnormal mitochondria were counted from two mice and five muscle fibers). Data is presented as mean ⁇ SEM; *** P ⁇ 0.001. Arrows indicate mitochondria with abnormal morphology. Scale bar indicates 500 nm.
  • FIGS 11A-E show mitochondrial uptake of the Ca 2+ indicator Rhod-2 AM in FDB muscle fiber.
  • a and B are shown images of an FDB muscle fiber loaded with the fluorescent indicators Rhod-2 (A) and Mitotracker Green (B).
  • the mitochondria are lined up along the sides of the z-lines.
  • C are shown overlap between the Ca 2+ indicator Rhod-2 and the mitochondrial marker Mitotracker Green.
  • the scale bar indicates 10 ⁇ .
  • In embodiment D are shown FK506-induced decrease in mitochondrial membrane potential.
  • the arrow indicates onset of FK506 (50 ⁇ ) treatment.
  • the dashed line indicates application of FCCP (300 nM).
  • Figure 12 shows EDL muscle fiber cross-sectional area in aged mice is not altered by 4 weeks of SI 07 treatment.
  • Figures 13A-C show increased open probability of RyRl-S2844D channels.
  • a and B are shown representative single channel current traces of RyRl -WT (A) and RyRl-S2844D (B) channels measured at 150 nM and 350 nM cytosolic [Ca 2+ ].
  • Channel openings are shown as upward deflections; the closed (c -) state of the channel is indicated by horizontal bars in the beginning of each tracing.
  • Example of channel activity is shown at two different time scales (5 s for the upper trace and 500 ms for the lower trace) as indicated by dimension bars, and the Po, To (average open time) and Tc (average closed time) are shown above each 5s trace.
  • An amplitude histogram is shown on the right side of each representative single channel trace to illustrate two to three distinct peaks corresponding to fully open ( ⁇ 4 pA), subconductance ( ⁇ 2 pA) and closed ( ⁇ 0 pA) states of the channel.
  • Figures 14A-C show strategy used to generate RyRl-S2844D mice.
  • A are shown targeted mutagenesis of RyRl Exon 53, the Loxp-Fret-Neo cassette was placed upstream of the point mutation in intron 52-53.
  • B are shown homologous recombination of the mutant RyRl-S2844D allele in ES cells and chimeric mice.
  • C are shown Cre mediated excision of the floxed neo cassette resulted in RyRl- S2844D knock-in mice.
  • EDL muscles from aged (24-month old) C57BL/6 mice were analyzed to explore the potential role of RyRl dysfunction in aging skeletal muscle.
  • ROS were measured in FDB fibers using a cell permeant form of the fluorescent indicator 20,70-dichlorodihydrofluorescein diacetate, acetyl ester (DCF) (Aydin et al, 2009; Durham et al., 2008). Muscle fibers from aged mice exhibited oxidative stress with significantly increased levels of DCF fluorescence compared to fibers from young adult mice (Fig. 8A, B).
  • FDB fibers loaded with Rhod-2 were used to measure mitochondrial Ca 2+ (Aydin et al, 2009; Bruton et al., 2003). Fibers were co-stained with Mitotracker Green to confirm that Rhod-2 was loaded into mitochondria (Fig. 11 A-C).
  • TMRE fluorescent indicator tetra-metyl rhodamine ethyl ester
  • TMRE fluorescence p-trifluoromethoxyphenylhydrazone
  • FCCP p-trifluoromethoxyphenylhydrazone
  • Rapamycin has other activities in addition to disrupting RyRl-calstabinl interactions such as inhibition of mTOR signaling.
  • FK506 similarly depletes calstabinl from RyRl channels, but does not inhibit mTOR (Brillantes et al., 1994) and caused a reduction in the TMRE signal similar to rapamycin (Fig. 1 ID).
  • rapamycin had no effect on mitochondrial membrane potential in FDB muscles from mice with a skeletal muscle targeted deficiency in FKBP12 (calstabinl) (Tang et al., 2004) (Fig. 1 IE). Together, these results indicate that inhibiting RyRl-calstabinl binding leads to Ca 2+ leak and mitochondrial dysfunction. Mitochondrial dysfunction is typically associated with increased ROS production.
  • SI 07 inhibits SR Ca 2+ leak by reducing the stress-induced depletion of calstabin from the RyR channel complex (Andersson and Marks, 2010; Bellinger et al., 2009; Lehnart et al., 2008).
  • SI 07 FDB fibers from young WT mice were incubated with SI 07 (5 ⁇ ) for 2-3 hours before the start of the experiment (Shan et al., 2010).
  • the rapamycin-induced increase in Rhod-2 fluorescence as well as the loss of mitochondrial membrane potential and increase in MitoSOX Red and DAF signals were prevented by SI 07 (Fig.
  • mice exhibited more episodes at higher running speeds (Fig. 3B).
  • S107-treated aged mice exhibited increased exercise capacity and exercised at higher intensity levels compared to controls.
  • S107 requires calstabinl to reduce Ca 2+ leak and improve muscle function
  • RyRl oxidation was measured in muscles from young (3 month) and aged (18 month) transgenic mice with mitochondrial targeted overexpression of catalase (MCAT) (Lee et al, 2010; Schriner et al, 2005).
  • MCAT catalase
  • RyRl oxidation was substantially reduced, nitrosylation slightly reduced and calstabinl binding was preserved in samples from aged MCAT mice compared to age-matched WT controls (Fig. 6G, H).
  • SR microsomes from WT muscle were treated with oxidizing (H 2 0 2 ) and nitrosylating (Noc-12) compounds alone and in combination to examine the effects of these modifications in more detail.
  • Senescent decline in muscle function is not restricted to mammals as the nematode C. elegans also develops a sarcopenia-like phenotype and impaired locomotion with age. Loss of muscular strength in aging is highly predictive of all-cause mortality in humans. Interestingly, this is also true for C. elegans, where the degree of locomotor dysfunction is a lifespan predictor. Thus, muscle dysfunction seems to be a central aspect of the aging process and studying pathogenic processes of sarcopenia might, therefore, provide clues as to the mechanisms of aging in general.
  • SNO protein modification is critically dependent on local production of NO, e.g., by NO synthases (NOS).
  • NOS NO synthases
  • ROS generation from non-mitochondrial sources e.g. non-phagocytic NAD(P)H oxidase (NOX)
  • NOX non-phagocytic NAD(P)H oxidase
  • the present study used saponin permeabilized muscle fibers in order to control the intracellular conditions (e.g., pH, [Ca 2+ ], [Mg 2+ ] and the Ca 2+ dye concentration), which is not possible using intact muscle fibers (Isaeva et al, 2005; Rios et al, 1999; Shirokova and Niggli, 2008).
  • This method was used previously to study pathological conditions where RyRl exhibited a leaky phenotype (Bellinger et al, 2009; Reiken et al, 2003; Ward et al, 2003).
  • the increased Ca 2+ spark frequency is consistent with the increased RyRl Po observed in the aged muscle.
  • Hypemitrosylated ryanodine receptor calcium release channels are leaky in dystrophic muscle. Nat Med 15, 325-330.
  • Insulin-like growth factor- 1 prevents age-related decrease in specific force and intracellular Ca2+ in single intact muscle fibres from transgenic mice. J Physiol 552, 833-844.
  • Muscle-specific inositide phosphatase (MIP/MTMR14) is reduced with age and its loss accelerates skeletal muscle aging process by altering calcium homeostasis. Aging (Albany NY) 2, 504-513.
  • Skeletal muscle ryanodine receptor is a redox sensor with a well defined redox potential that is sensitive to channel modulators. J Biol Chem 275, 36556-36561.
  • Skeletal muscle sarcoplasmic reticulum contains a NADH-dependent oxidase that generates superoxide. Am J Physiol Cell Physiol 285, C215-221.
  • Hypemitrosylated ryanodine receptor calcium release channels are leaky in dystrophic muscle. Nat Med 15, 325-330.

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Abstract

La présente invention concerne des méthodes et des compositions adaptées au traitement prophylactique et/ou thérapeutique de la sarcopénie. Les compositions incluent un ou plusieurs des composés suivants : benzothiazépine, benzoxazépine, benzodiazépine ou benzazépine comme décrit dans la présente, tandis que les méthodes incluent l'administration d'une quantité thérapeutiquement ou prophylactiquement active des composés ou des compositions à un sujet en ayant besoin.
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