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WO2018091689A1 - Inducteurs d'hypertrophie du muscle squelettique - Google Patents

Inducteurs d'hypertrophie du muscle squelettique Download PDF

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Publication number
WO2018091689A1
WO2018091689A1 PCT/EP2017/079669 EP2017079669W WO2018091689A1 WO 2018091689 A1 WO2018091689 A1 WO 2018091689A1 EP 2017079669 W EP2017079669 W EP 2017079669W WO 2018091689 A1 WO2018091689 A1 WO 2018091689A1
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Prior art keywords
compound
formula
use according
muscle
hydrogen
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Inventor
Pauline POYDENOT
Joris MICHAUD
Mélanie FLAENDER
Eve DUCHEMIN-PELLETIER
Luc Selig
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CYTOO
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CYTOO
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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • 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 present invention relates to therapeutic strategies to induce skeletal muscle hypertrophy, prevent atrophy or treat or prevent diseases or injuries resulting in loss of skeletal muscle tissue and/or muscle weakness. It also relates to a non-therapeutic use of skeletal muscle hypertrophy inducers.
  • Muscle wasting and weakness may result from a large panel of disease states and conditions including metabolic diseases, neurologic diseases, muscle diseases, acute or chronic illness (cachexia), aging, inactivity, food starvation and even poisoning.
  • cachexia chronic illness
  • aging inactivity
  • food starvation even poisoning.
  • extensive research has led to a better understanding of the signalling pathways implicated in the loss of muscle mass.
  • the offer of therapeutic strategies directly targeting the muscle remains poor.
  • Muscle loss may occur, in particular, with aging and is a component of the frailty syndrome. Named "sarcopenia", this degenerative loss results in direct muscle atrophy and carries an increased risk for poor health outcomes including falls, incident disability, hospitalization, and mortality. With a growing older population, sarcopenia is an ever increasing global health concern and there has been great interest in developing approaches to counteract the effects of sarcopenia, and thereby reduce the age-related decline and disability. Potential interventions for sarcopenia may include physical activity and nutritional supplementation but, to date, pharmacological interventions have shown limited efficacy.
  • Muscle weakness can also directly result from neuromuscular disorders such as myopathies, neuromuscular junction diseases or motor neuron diseases.
  • Myopathies are neuromuscular disorders in which the primary symptom is muscle weakness due to dysfunction of skeletal muscle fibres.
  • Myopathies can be inherited or acquired and include, for example, muscular dystrophies, metabolic myopathies such as mitochondrial myopathies or drug-induced myopathies, and autoimmune myopathies such as dermatomyositis, polymyositis or inclusion body myositis.
  • DMD Duchenne Muscular Dystrophy
  • the object of the present invention is to provide new therapeutic strategies to induce skeletal muscle hypertrophy, prevent muscular atrophy, promote skeletal muscle regeneration and treat or prevent skeletal muscle wasting.
  • R2 is selected from the group consisting of hydrogen, a C 4 -C 6 cycloalkyl optionally substituted by a hydroxyl group, and -(CH 2 ) n -R.5 wherein n is 0, 1, 2 or 3 and R5 is a phenyl group substituted by -NH2 or a halogen; and
  • R3 is hydrogen or -NH(CH2) m R6 wherein m is 0, 1 or 2 and R 6 is a phenyl group, with the proviso that R3 is not hydrogen when Ri is -CH2OH and R2 is hydrogen, or any pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof,
  • skeletal muscle hypertrophy inducer for use as skeletal muscle hypertrophy inducer, preferably in a subject suffering from a disease or disorder resulting in loss of skeletal muscle tissue and/or muscle weakness.
  • It also relates to a compound of formula (I) as defined above, or any pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, for use to promote skeletal muscle regeneration and/or prevent skeletal muscle atrophy, preferably in a subject suffering from a disease or disorder resulting in loss of skeletal muscle tissue and/or muscle weakness.
  • R2 is selected from the group consisting of hydrogen, a cyclopentyl optionally substituted by a hydroxyl group, and -(CH 2 )n-Rs wherein n is 1 or 2 and R5 is a phenyl group substituted by -NH2 or iodine
  • R3 is hydrogen or -NHR 6 with R 6 being a phenyl group.
  • R2 is selected from the group consisting of hydrogen, a C4-C6 cycloalkyl optionally substituted by a hydroxyl group, and -(CH 2 )n-Rs wherein n is 0, 1, 2 or 3 and R5 is a phenyl group substituted by -NH2.
  • R2 is selected from the group consisting of hydrogen, a cyclopentyl optionally substituted by a hydroxyl group, and -(CH 2 )n-Rs wherein n is 1 or 2 and R5 is a phenyl group substituted by -NH2; and R3 is hydrogen or -NHR 6 with R 6 being a phenyl group.
  • R3 is -NHR 6 with R 6 being a phenyl group.
  • R2 is -(CH2)n-R5 wherein n is 1 or 2 and R5 is a phenyl group substituted by -NH2; and
  • R3 is hydrogen.
  • Ri is -CH2OH
  • R2 is a cyclopentyl optionally substituted by a hydroxyl group
  • R3 is hydrogen
  • R2 is - (CH 2 )n-Rs wherein n is 1 or 2 and R5 is a phenyl group substituted by -NH2
  • R3 is hydrogen
  • R2 is selected from the group consisting of hydrogen and a cyclopentyl optionally substituted by a hydroxyl group; and
  • R3 is hydrogen or -NHR 6 with R 6 being a phenyl group.
  • the compound of formula I may be selected from the group consisting of
  • nosine 2- phenylaminoadenosine, GR79236X and NECA, more preferably from the group consisting of AB-MECA, APNEA, N6-cyclopentyladenosine, 2-phenylaminoadenosine and GR79236X.
  • the compound of formula I is an adenosine Al receptor agonist selected from the group consisting of NECA, N6-cyclopentyladenosine, 2- phenylaminoadenosine and GR79236X, preferably from the group consisting of NECA, 2- phenylaminoadenosine and GR79236X, and more preferably from the group consisting of NECA and GR79236X.
  • the compound of formula I is GR79236X.
  • the disease or disorder resulting in loss of skeletal muscle tissue and/or muscle weakness may be selected from neuromuscular diseases, cachexia, sarcopenia, muscle disuse atrophy, atrophy induced by anorexia food starvation, and muscle injuries including acute muscular injury or muscle overuse injury, preferably selected from neuromuscular diseases, cachexia and sarcopenia, more preferably is sarcopenia or cachexia, even more preferably sarcopenia.
  • the present invention also relates to a product containing a compound of formula (I) as defined above, and a compound inducing skeletal muscular atrophy, as a combined preparation for simultaneous, separate or sequential use.
  • the compound inducing skeletal muscular atrophy is a therapeutic agent, more preferably selected from the group consisting of corticosteroids, colchicine, chloroquine, hydroxychloroquine, D-penicillamine, antibiotics, betablockers, amiodarone, cimetidine, zidovudine, vincristine, clofibrate, statins, fibrates, cyclosporine, L-tryptophan, drugs causing hypokalaemia, lipid lowering agents, and therapeutic agents administered by intramuscular route such as vaccines, and even more preferably is a lipid lowering agent, such as statins and fibrates.
  • a therapeutic agent such as statins and fibrates.
  • the present invention also relates to a non-therapeutic use of a compound of formula (I) as defined above, to increase muscle mass, muscle strength and/or muscle performance in a subject, and in particular to increase skeletal muscle mass, skeletal muscle strength and/or skeletal muscle performance in a subject.
  • the present invention also relates to the use, preferably the non-therapeutic use, of a compound of formula (I) as defined above, to prevent loss of skeletal muscle mass in a subject, or as ingredient or additive for animal feed composition.
  • the present invention further relates to a method of improving livestock performance comprising providing to said livestock a compound of formula (I) as defined above, preferably a feed composition, ingredient, additive, or dietary supplement comprising a compound of formula (I) as defined above.
  • the present invention relates to the use of such compounds as skeletal muscle hypertrophy inducers, to promote skeletal muscle regeneration, to prevent skeletal muscle atrophy, or in the treatment or prevention of a disease or injury resulting in loss of skeletal muscle tissue and/or muscle weakness.
  • the resent invention thus relates to a compound of formula (I)
  • R2 is selected from the group consisting of hydrogen, a C 4 -C 6 cycloalkyl optionally substituted by a hydroxyl group, and -(CH 2 ) n -R.5 wherein n is 0, 1, 2 or 3 and R5 is a phenyl group substituted by -NH2 or a halogen; and
  • R3 is hydrogen or -NH(CH2) m R6 wherein m is 0, 1 or 2 and R 6 is a phenyl group, with the proviso that R3 is not hydrogen when Ri is -CH2OH and R2 is hydrogen, or any pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof,
  • alkyl refers to a univalent radical containing only carbon and hydrogen atoms arranged in a chain.
  • (Ci-C3)-alkyl groups include methyl, ethyl, propyl, or isopropyl.
  • the (Ci-C3)-alkyl group is methyl of ethyl, more preferably methyl.
  • cycloalkyl refers to a cyclic chain hydrocarbon radical with only single carbon-carbon bonds.
  • C4-C6) cycloalkyl groups include cyclobutyl, cyclopentyl and cyclohexyl.
  • the (C4-C6) cycloalkyl group is cyclopentyl.
  • R2 is a cyclopentyl substituted by a hydroxyl group
  • NH 2 is in para position.
  • halogen is in meta position.
  • R2 is selected from the group consisting of hydrogen, a cyclopentyl optionally substituted by a hydroxyl group, and -(CH 2 )n-Rs wherein n is 1 or 2 and R5 is a phenyl group substituted by -NH2 or a halogen, preferably iodine; and
  • R3 is hydrogen or -NHR 6 with R 6 being a phenyl group.
  • the compound of formula (I) has one or several of the following features:
  • R2 is selected from the group consisting of hydrogen, a cyclopentyl optionally substituted by a hydroxyl group, and -(CH 2 )n-Rs wherein n is 1 or 2 and R5 is a phenyl group substituted by -NH2 or a halogen, preferably iodine; and
  • R3 is hydrogen or -NHR 6 with R 6 being a phenyl group.
  • the compound of formula (I) may meet one feature, two features [for instance a) and b); a) and c); b) and c)], or three features [i.e. a), b) and c)] as described above.
  • R2 is selected from the group consisting of hydrogen, a cyclopentyl optionally substituted by a hydroxyl group, and -(CH 2 )n-Rs wherein n is 1 or 2 and R5 is a phenyl group substituted by -NH2 or iodine; and
  • R3 is hydrogen or -NHR 6 with R 6 being a phenyl group.
  • R2 is selected from the group consisting of hydrogen, a cyclopentyl optionally substituted by a hydroxyl group, and -(CH 2 )n-Rs wherein n is 1 or 2 and R5 is a phenyl group substituted by -NH2; and
  • R3 is hydrogen or -NHR 6 with R 6 being a phenyl group.
  • R2 is selected from the group consisting of hydrogen, -(CH 2 )n-Rs wherein n is 1 or 2, preferably 2, and R5 is a phenyl group substituted by -NH2, and a cyclopentyl optionally substituted by a hydroxyl group; and
  • R3 is hydrogen or -NH(CH2) m R6 wherein m is 0, 1 or 2, preferably 0, and R 6 is a phenyl group.
  • R2 is a cyclopentyl optionally substituted by a hydroxyl group
  • R3 is hydrogen
  • R2 is selected from the group consisting of hydrogen and -(CH 2 )n-Rs wherein n is 1 or 2 and R5 is a phenyl group substituted by -NH2 or a halogen, preferably iodine; and
  • R3 is hydrogen
  • R2 is selected from the group consisting of hydrogen and -(CH 2 )n-Rs wherein n is 1 or 2 and R5 is a phenyl group substituted by -NH2.
  • R2 is -(CH 2 )n-Rs wherein n is 1 or 2 and R5 is a phenyl group substituted by -NH2 or a halogen, preferably iodine; and
  • R3 is hydrogen
  • R2 is -(CH 2 )n-Rs wherein n is 1 or 2 and R5 is a phenyl group substituted by -NH2.
  • n is 1 or 2
  • R5 is a phenyl group substituted by -NH2.
  • R2 is hydrogen
  • R3 is hydrogen or -NH(CH2) m R6 wherein m is 0, 1 or 2, preferably 0, and R 6 is a phenyl group.
  • R2 is selected from the group consisting of hydrogen, a cyclopentyl optionally substituted by a hydroxyl group, and -(CH 2 )n-Rs wherein n is 1 or 2 and R5 is a phenyl group substituted by -NH2 or a halogen, preferably iodine; and
  • R3 is hydrogen
  • R2 is -(CH 2 )n-Rs wherein n is 1 or 2 and R5 is a phenyl group substituted by -NH2.
  • R2 is selected from the group consisting of hydrogen and a cyclopentyl optionally substituted by a hydroxyl group; and
  • R3 is hydrogen or -NHR 6 with R 6 being a phenyl group.
  • the compound of formula (I) is selected from the group consisting of or any pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof.
  • the compound of formula (I) may be selected from the group consisting of AB-MECA, APNEA, N6-cyclopentyladenosine, GR79236X, NECA and 2- phenylaminoadenosine, or any pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, preferably from the group consisting of APNEA, GR79236X, NECA
  • the compound of formula (I) may also be selected from the group consisting of AB- MECA, APNEA, N6-cyclopentyladenosine, 2-phenylaminoadenosine and GR79236X, or any pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, preferably from APNEA, GR79236X.
  • the compound of formula (I) may also be selected from the group consisting of IB-MECA, APNEA, GR79236X and NECA, or any pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof.
  • the compound of formula I is an adenosine Al receptor agonist selected from the group consisting of NECA, N6-cyclopentyladenosine, 2- phenylaminoadenosine and GR79236X, preferably from the group consisting of NECA, 2- phenylaminoadenosine and GR79236X, and more preferably from the group consisting of NECA and GR79236X.
  • the compound of formula I is GR79236X.
  • the compounds of formula (I) as described above may be used in the form of pharmaceutically acceptable salts, hydrates and solvates.
  • Said pharmaceutically acceptable salts, hydrates and solvates of Formula (I) compounds may be formed, where appropriate, by methods well known to those of skill in the art.
  • pharmaceutically acceptable salt refers to salts which are non-toxic for a patient and suitable for maintaining the stability of a therapeutic agent and allowing the delivery of said agent to target cells or tissue.
  • Pharmaceutically acceptable salts are well known in the art.
  • solvate refers to a solvent addition form that contains either stoichiometric or non stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water, the solvate formed is a hydrate. When the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one of the substances in which the water retains its molecular state as H2O, such combination being able to form one or more hydrates.
  • the compounds of formula (I) as described above may also be used in the form of a prodrug.
  • Prodrugs are generally drug precursors that, following administration to an individual and subsequent absorption, are converted to an active, or a more active species via some process, such as conversion by a metabolic pathway.
  • Some prodrugs have a chemical group present on the prodrug that, for example, renders it less active, increases its solubility and/or improves safety profiles over administration of the parent drugs.
  • the prodrugs may be less susceptible to in vivo degradation and exhibit a greater half-life than its parent drug.
  • Prodrugs are often useful because, in some situations, they are easier to administer than the parent drug. They are, for instance, bioavailable by oral administration whereas the parent is not. In certain instances, the prodrug also has improved solubility in pharmaceutical compositions over the parent drug.
  • An example, without limitation, of a prodrug would be a compound as described herein which is administered and subsequently subjected to a biotransformation in vivo and thus provides a therapeutically effective concentration of an active agent.
  • Bundgaard “Design and Application of Prodrugs” in A Textbook of Drug Design and Development, Krosgaard- Larsen and Bundgaard, Ed., 1991, Chapter 5, 113-191, which is incorporated herein by reference.
  • Prodrugs may be prepared, for example, by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) according to the invention and as described above, or any pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, and a pharmaceutically acceptable carrier and/or excipient, preferably for use as skeletal muscle hypertrophy inducer.
  • composition of the invention is formulated in accordance with standard pharmaceutical practice (see, e.g., Remington: The Science and Practice of Pharmacy (20th ed.), ed. A. R. Gennaro, Lippincott Williams & Wilkins, 2000 and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York) known by a person skilled in the art.
  • standard pharmaceutical practice see, e.g., Remington: The Science and Practice of Pharmacy (20th ed.), ed. A. R. Gennaro, Lippincott Williams & Wilkins, 2000 and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York
  • Possible pharmaceutical compositions include those suitable for oral, transmucosal (including nasal, rectal or vaginal), topical (including transdermal, buccal and sublingual), or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.
  • transmucosal including nasal, rectal or vaginal
  • topical including transdermal, buccal and sublingual
  • parenteral including subcutaneous, intramuscular, intravenous and intradermal
  • the pharmaceutical composition of the invention is suitable for oral administration.
  • compositions for parenteral administration are generally physiologically compatible sterile solutions or suspensions which can optionally be prepared immediately before use from solid or lyophilized form.
  • Adjuvants such as a local anesthetic, preservative and buffering agents can be dissolved in the vehicle and a surfactant or wetting agent can be included in the composition to facilitate uniform distribution of the active ingredient.
  • the composition can be formulated into conventional oral dosage forms such as tablets, capsules, powders, granules and liquid preparations such as syrups, elixirs, and concentrated drops.
  • Non toxic solid carriers or diluents may be used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, glucose, sucrose, magnesium, carbonate, and the like.
  • binders which are agents which impart cohesive qualities to powdered materials are also necessary.
  • starch, gelatine, sugars such as lactose or dextrose, and natural or synthetic gums can be used as binders.
  • Disintegrants are also necessary in the tablets to facilitate break-up of the tablet.
  • Disintegrants include starches, clays, celluloses, algins, gums and crosslinked polymers.
  • lubricants and glidants are also included in the tablets to prevent adhesion to the tablet material to surfaces in the manufacturing process and to improve the flow characteristics of the powder material during manufacture.
  • Colloidal silicon dioxide is most commonly used as a glidant and compounds such as talc or stearic acids are most commonly used as lubricants.
  • composition can be formulated into ointment, cream or gel form and appropriate penetrants or detergents could be used to facilitate permeation, such as dimethyl sulfoxide, dimethyl acetamide and dimethylformamide.
  • nasal sprays for transmucosal administration, nasal sprays, rectal or vaginal suppositories can be used.
  • the active compound can be incorporated into any of the known suppository bases by methods known in the art. Examples of such bases include cocoa butter, polyethylene glycols (carbowaxes), polyethylene sorbitan monostearate, and mixtures of these with other compatible materials to modify the melting point or dissolution rate.
  • composition according to the invention may be formulated to release the active drug substantially immediately upon administration or at any predetermined time or time period after administration.
  • composition according to the invention can comprise one or more compound of formula (I) of the invention and as described above associated with one or several pharmaceutically acceptable excipients and/or carriers. These excipients and/or carriers are chosen according to the form of administration as described above.
  • composition according to the invention may also comprise one or several additional active compounds.
  • Said additional active compounds may be selected, for example, from the group consisting of anti-inflammatories, protein anabolic agents (e.g. growth hormone or insulin-like growth factor I), antineoplastic agents, antibiotics, local anesthetics, anabolic/androgenic steroids (e.g. testosterone), glucocorticoids, appetite stimulants (e.g. dronabinol), cytokine modulators (e.g. thalidomide), angiotensin and beta-adrenoreceptor inhibitors, NHE-1 inhibitors (e.g. rimeporide), antifibrotic drugs (e.g.
  • losartan or Lisinopril phosphodiesterase 5 (PDE5) inhibitors (e.g tadalafil or sildenafil), dehydroepiandrosterone, Vitamin D, ursolic acid, omega 3 acids, angiotensin-converting enzyme (ACE) inhibitors, proteasome inhibitors, cyclophilin D inhibitors, PGC-1 a (alpha) pathway modulators, myostatin and activin A antagonists, ghrelin agonists, p2-adrenoreceptor agonists, creatine supplements, antifibrotic drugs such as losartan and lisinopril, muscle ischemia therapies such as tadalafil and sildenafil, mutation specific therapies such as exon skipping therapies (e.g.
  • eteplirsen a morpholino phosphorodiamidate antisense oligomer targeting mutations implicated in DMD cases
  • agents for therapeutic nonsense suppression such as ataluren, utrophin upregulators such as SMT-C1100.
  • the present invention relates to a compound of formula (I) or any pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, or a pharmaceutical composition according to the invention and as described above, for use as skeletal muscle hypertrophy inducer.
  • Skeletal muscle fibers are syncytia that arise from the sequential fusion of myoblast cells.
  • the process involves i) the differentiation of myoblasts into myocytes, ii) the fusion of myocytes to form nascent myotubes and iii) additional fusion of myocytes with nascent myotubes to form more mature myotubes.
  • the expression « skeletal muscle hypertrophy » refers to a gain of skeletal muscle mass characterized by an increase in the size of pre-existing myofibers and/or an increase in the number of myofibers and/or an increase in the mean number of nuclei per myotube and/or an increase in the fusion index (number of nuclei in myotubes divided by total number of nuclei in myoblasts and myotubes).
  • the expression « skeletal muscle hypertrophy » refers to an increase in the size of pre-existing myofibers and/or an increase in the number of myofibers and/or an increase in the fusion index.
  • the terms "myotube” and "myofiber” are used interchangeably.
  • the present invention also relates to a method for inducing skeletal muscle hypertrophy in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I) or any pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, or a pharmaceutical composition according to the invention and as described above, to said subject.
  • the therapeutically effective amount to be administered may be easily chosen by the skilled person and should be sufficient to provide an increase of skeletal muscle mass or skeletal muscle strength in the subject.
  • the subject is an animal, preferably a mammal, more preferably a human being.
  • the subject is a subject suffering from muscle wasting or weakness resulting from a disease or disorder resulting in loss of skeletal muscle tissue and/or skeletal muscle weakness, such as diseases or disorders described below.
  • the present invention further concerns the use of a compound of formula (I), or any pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, or a pharmaceutical composition according to the invention and as described above, for preparing a medicament inducing skeletal muscle hypertrophy.
  • the present invention also relates to a compound of formula (I) or any pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, or a pharmaceutical composition according to the invention and as described above, for use to prevent involuntary loss of skeletal muscle mass, preferably due to the degeneration of muscle fibers, for use to promote or stimulate skeletal muscle mass increase, for use to replete skeletal muscle mass and/or for use to increase skeletal muscle mass and/or strength.
  • the present invention also relates to a method for preventing involuntary loss of skeletal muscle mass, preferably due to the degeneration of muscle fibers, promoting or stimulating skeletal muscle mass increase, repleting skeletal muscle mass and/or increasing skeletal muscle mass and/or strength, in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I) or any pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, or a pharmaceutical composition according to the invention and as described above, to said subject.
  • the therapeutically effective amount to be administered may be easily chosen by the skilled person and should be sufficient to prevent involuntary loss of skeletal muscle mass, to promote or stimulate skeletal muscle mass increase, to replete skeletal muscle mass and/or to increase skeletal muscle mass and/or strength.
  • the subject may be as defined above.
  • the present invention further concerns the use of a compound of formula (I), or any pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, or a pharmaceutical composition according to the invention and as described above, for preparing a medicament preventing involuntary loss of skeletal muscle mass, preferably due to the degeneration of muscle fibers, promoting or stimulating skeletal muscle mass increase, repleting skeletal muscle mass and/or increasing skeletal muscle mass and/or strength.
  • compound of formula (I) according to the invention and described above are not only able to promote the differentiation of myoblasts into myotubes and to increase the fusion index reflecting the capacity of cells to regenerate, but are also able to prevent skeletal muscle atrophy, in particular atrophy induced by IL- ⁇ , TNF-a, myostatin, TGF- ⁇ or dexamethasone.
  • the present invention also relates to a compound of formula (I) or any pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, or a pharmaceutical composition according to the invention and as described above, for use to promote skeletal muscle regeneration and/or prevent skeletal muscle atrophy.
  • skeletal muscle regeneration refers to the capacity of muscle cells or tissue to regenerate, i.e. to produce new myotubes from myoblasts.
  • the expression “to promote skeletal muscle regeneration” thus refers to the capacity of compounds of formula (I) to promote differentiation of myoblasts into myotubes and/or to increase the number of myotubes and/or to improve the regeneration capacity of muscle tissue and in particular of myotubes.
  • the expression "to prevent skeletal muscle atrophy” refers to the capacity of compounds of formula (I) to prevent, stop or slow down muscle wasting.
  • Muscle atrophy may be caused for example by a disease state, a particular physiological condition such as aging, food starvation or inactivity, or an atrophying agent such as drug (statins) or poison (botulinum toxin).
  • Prevention of muscle atrophy is preferably obtained by increasing the production of muscle mass and then counter balancing muscle loss.
  • the present invention also relates to a method for promoting skeletal muscle regeneration and/or preventing skeletal muscle atrophy in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I) or any pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, or a pharmaceutical composition according to the invention and as described above, to said subject.
  • the therapeutically effective amount to be administered may be easily chosen by the skilled person and should be sufficient to stimulate skeletal muscle regeneration and/or prevent, stop or slow down muscle wasting, preferably by increasing the production of muscle mass and then counter balancing muscle loss.
  • the subject may be as defined above.
  • the present invention further relates to the use of a compound of formula (I) or any pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, or a pharmaceutical composition according to the invention and as described above, for preparing a medicament for promoting skeletal muscle regeneration and/or preventing skeletal muscle atrophy.
  • the present invention further relates to a compound of formula (I) or any pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, or a pharmaceutical composition according to the invention and as described above, for use in the treatment or prevention of muscle wasting, and in particular in the treatment or prevention of a disease or disorder resulting in loss of skeletal muscle tissue and/or skeletal muscle weakness.
  • treatment refers to any act intended to ameliorate the health status of patients such as therapy, prevention, prophylaxis and retardation of the disease.
  • such term refers to the amelioration or eradication of a disease or symptoms associated with a disease.
  • this term refers to minimizing the spread or worsening of the disease resulting from the administration of one or more therapeutic agents to a subject with such a disease.
  • treatment of muscle wasting may refer to the therapy, prevention or retardation of involuntary loss of skeletal muscle mass, preferably due to the degeneration of muscle fibers.
  • treatment of a disease or disorder resulting in loss of skeletal muscle tissue and/or skeletal muscle weakness may refer to a preservation or increase of the skeletal muscle mass and/or the skeletal muscle strength of a patient or a slow-down of the skeletal muscle mass loss and/or the skeletal muscle strength loss of a patient.
  • the effective amount may be a therapeutically or prophylactically effective amount.
  • a “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result.
  • the therapeutically effective amount may vary according to factors such as the disease or disorder, disease state, age, sex, and weight of the individual.
  • a therapeutically effective amount encompasses an amount in which any toxic or detrimental effects are outweighed by the therapeutically beneficial effects.
  • a “prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, but not necessarily, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount would be less than the therapeutically effective amount.
  • the disease or disorder to be treated may be any disease or disorder resulting in loss of skeletal muscle tissue or mass and/or skeletal muscle weakness.
  • Muscle wasting i.e. loss of skeletal muscle tissue
  • weakness may result from a large panel of diseases or disorders such as metabolic diseases (e.g. glycogen storage diseases, lipid storage diseases or disorders of purine nucleotide metabolism), neurologic diseases (e.g. Hereditary Sensory and Motor Neuropathies type III) and neuromuscular diseases, cachexia (i.e. muscle atrophy resulting from diseases such as cancer, AIDS, congestive heart failure, chronic obstructive pulmonary disease, severe burns, renal failure or liver failure), sarcopenia, muscle disuse atrophy (i.e.
  • metabolic diseases e.g. glycogen storage diseases, lipid storage diseases or disorders of purine nucleotide metabolism
  • neurologic diseases e.g. Hereditary Sensory and Motor Neuropathies type III
  • cachexia i.e. muscle atrophy resulting from diseases such as cancer, AIDS, congestive heart failure, chronic obstructive pulmonary disease, severe burns, renal failure or liver failure
  • the disease or disorder to be treated is selected from neuromuscular diseases, cachexia, sarcopenia, muscle disuse atrophy, atrophy induced by anorexia food starvation, and muscle injuries including acute muscular injury or muscle overuse injury. More preferably, the disease or disorder to be treated is selected from neuromuscular diseases, cachexia and sarcopenia.
  • the disease or disorder is a neuromuscular disease, preferably selected from muscle diseases (i.e. myopathies), neuromuscular junction diseases or motor neuron diseases.
  • Myopathies are neuromuscular disorders in which the primary symptom is muscle weakness due to dysfunction of skeletal muscle fibres.
  • Myopathies can be inherited or acquired and include, for example, muscular dystrophies, metabolic myopathies such as mitochondrial myopathies or drug-induced myopathies, and autoimmune myopathies such as dermatomyositis, polymyositis or inclusion body myositis.
  • Muscular dystrophies represent a large group of myopathies causing a progressive degeneration of myo fibers and resulting in a loss of muscle mass. Mutations in over 30 genes causing muscular dystrophies have been identified. Examples of muscular dystrophies include, but are not limited to Duchenne muscular dystrophy, Becker muscular dystrophy, congenital muscular dystrophies, facioscapulohumeral muscular dystrophies, myotonic muscular dystrophies, distal muscular dystrophies such as Miyoshi muscular dystrophy, Emery-Dreifuss muscular dystrophy, limb-girdle muscular dystrophies and oculopharyngeal muscular dystrophies.
  • Motor neuron diseases are disorders which are characterized by the gradual degeneration and death of motor neurons which control voluntary muscles. Motor neurons thus stop sending messages to muscles which gradually weaken and atrophy. Motor neuron diseases include, for example, amyotrophic lateral sclerosis, primary lateral sclerosis, progressive muscular atrophy, progressive bulbar palsy, pseudobulbar palsy and spinal muscular atrophies.
  • Neuromuscular junction diseases are disorders which have in common the perturbation of the neurotransmission through the neuromuscular junction and result in progressive weakness due to a reduced muscle strength.
  • Neuromuscular junction diseases include, for example, myasthenia gravis, autoimmune neuromyotonia (Isaacs' syndrome), Lambert-Eaton myasthenic syndrome, or may result of a form of poison that effects neuromuscular junction functioning such as snake venom or neurotoxins (e.g Clostridium botulinum toxin).
  • the neuromuscular disease is selected from muscular dystrophies, and in particular from Duchenne muscular dystrophy, Becker muscular dystrophy, myotonic muscular dystrophies, distal muscular dystrophies such as Miyoshi muscular dystrophy, and limb-girdle muscular dystrophies.
  • the disease or disorder is selected from cachexia and sarcopenia, preferably is sarcopenia.
  • the compound of formula (I) or any pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, or a pharmaceutical composition according to the invention and as described above may be used in combination with other active ingredients that can be chosen according to the disease to be prevented or treated.
  • active ingredients include, but are not limited to, antiinflammatories, protein anabolic agents (e.g. growth hormone or insulin-like growth factor I), antineoplastic agents, antibiotics, local anesthetics, anabolic/androgenic steroids (e.g. testosterone), glucocorticoids, appetite stimulants (e.g. dronabinol), cytokine modulators (e.g.
  • thalidomide angiotensin and beta-adrenoreceptor inhibitors
  • NHE-1 inhibitors e.g. rimeporide
  • antifibrotic drugs e.g. losartan or Lisinopril
  • PDE5 inhibitors e.g tadalafil or sildenafil
  • dehydroepiandrosterone Vitamin D, ursolic acid, omega 3 acids
  • angiotensin-converting enzyme (ACE) inhibitors proteasome inhibitors, cyclophilin D inhibitors
  • PGC-1 a (alpha) pathway modulators myostatin and activin A antagonists, ghrelin agonists, 2-adrenoreceptor agonists, creatine supplements, antifibrotic drugs such as losartan and lisinopril, muscle ischemia therapies such as tadalafil and sildenafil, mutation specific therapies such as exon skipping therapies (e.g.
  • eteplirsen a morpholino phosphorodiamidate antisense oligomer targeting mutations implicated in DMD cases
  • agents for therapeutic nonsense suppression such as ataluren, utrophin upregulators such as SMT-Cl lOO, gene replacement therapies (such as using rAAV2.5-CMV-Mini-dystrophy, rAAVrh74.MCK.Mini- dystrophy or rAAVl.CMV.huFollistatin344) or cell therapies using muscle precursor cells or stem cells.
  • combination therapies noted above encompass combined administration (where two or more therapeutic agents are included in the same or separate formulations), and separate administration, in which case, administration of the compound of formula (I) can occur prior to, simultaneously, and/or following, administration of the additional therapeutic agent.
  • the compound of formula (I) (and any additional therapeutic agent) can be administered by any suitable means, including parenteral, oral, transmucosal or topical administration, preferably oral administration.
  • the doses used for the administration can be adapted as a function of various parameters, and in particular as a function of the mode of administration used, of the relevant pathology, or alternatively of the desired duration of treatment.
  • the compound of formula (I) (and any additional therapeutic agent) may be administered as a single dose or in multiple doses.
  • the amount of compound of formula (I) which will be effective in the treatment of a particular disorder or condition will depend on the nature of the disorder or condition, and can be determined by standard clinical techniques.
  • each dose may range from about 0.05 mg to about 100 mg per kilogram of body weight of compound of formula (I), preferably from about 0.1 mg to about 50 mg per kilogram of body weight, more preferably from about 0.25 mg to about 10 mg per kilogram of body weight of compound of formula (I), and even more preferably from about 0.1 mg to about 5 mg per kilogram of body weight of compound of formula (I).
  • the dosing schedule for administration may vary from once a month to daily depending on a number of clinical factors, including the type of disease, severity of disease, and the subject's sensitivity to the therapeutic agent. As shown in the experimental section, the compounds of formula (I) of the invention and as described above are able to prevent muscle atrophy.
  • the present invention thus also concerns a product containing a compound of formula (I) or any pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, as described above and a compound inducing skeletal muscular atrophy, as a combined preparation for simultaneous, separate or sequential use.
  • the compound inducing skeletal muscular atrophy is a therapeutic agent.
  • the compound of formula (I) or any pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof is used to prevent or limit drug-induced myopathy.
  • the present invention further concerns a method for preventing or limiting the skeletal muscular atrophy induced by a therapeutic agent in a subject comprising administering a therapeutically effective amount of a compound of formula (I) or any pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, as described above to said subject simultaneously, separately or sequentially to the administration of said therapeutic agent inducing skeletal muscular atrophy.
  • therapeutic agents inducing skeletal muscular atrophy include, but are not limited to corticosteroids, colchicine, chloroquine, hydroxychloroquine, D-penicillamine, antibiotics, betablockers, amiodarone, cimetidine, zidovudine, vincristine, clofibrate, statins, fibrates, cyclosporine, L-tryptophan, drugs causing hypokalaemia and lipid lowering agents, or combinations of drugs such as a fibrate and a statin or cyclosporin and colchicin, and therapeutic agents administered by intramuscular route such as vaccines.
  • the therapeutic agent inducing skeletal muscular atrophy include is a lipid lowering agent, preferably selected from statins and fibrates.
  • the compound of formula (I) and the therapeutic agent inducing skeletal muscular atrophy may be administered simultaneously.
  • the compound of formula (I) may be administered to the subject prior or after administration of the therapeutic agent inducing skeletal muscular atrophy.
  • the therapeutic agent and the compound of formula (I) are administered separately, they are both administered within 24 hours.
  • Compounds of formula (I) of the invention and as described above, i.e. skeletal muscle hypertrophy inducers, may also find applications in feed and food industries, in particular as dietary supplements.
  • the present invention also relates to a dietary supplement co of formula (I)
  • R2 is selected from the group consisting of hydrogen, a C 4 -C 6 cycloalkyl optionally substituted by a hydroxyl group, and -(CH 2 ) n -R.5 wherein n is 0, 1, 2 or 3 and R5 is a phenyl group substituted by -NH2 or a halogen; and
  • R3 is hydrogen or -NH(CH2) m R6 wherein m is 0, 1 or 2 and R 6 is a phenyl group, with the proviso that R3 is not hydrogen when Ri is -CH2OH and R2 is hydrogen, or any acceptable salt, hydrate, solvate or prodrug thereof.
  • the subject is preferably a mammal, more preferably a human being.
  • the subject is a non-human animal, preferably a mammal, and even more preferably a livestock animal or a sports or leisure animal, e.g. racehorses.
  • Livestock animals are non-human mammals, preferably mammals used for meat.
  • livestock animals may be selected from pig, cattle, goat, sheep, horse, bison, deer, elk or moose.
  • the subject is a human being, preferably an adult human.
  • the subject is an older adult human, e.g. of more than 60, and the dietary supplement composition is used, or is suitable, to stop, slow/down or prevent muscle function and/or mass decline.
  • the subject is preferably a healthy subject, i.e. a subject who is not suffering from a disease or disorder resulting in loss of skeletal muscle tissue and/or muscle weakness.
  • the dietary supplement composition may be in the form of a powder, liquid, or solid.
  • the dietary supplement composition is formulated for oral administration.
  • said dietary supplement composition may be formulated into conventional oral dosage forms such as tablets, capsules, powders, granules and liquid preparations such as syrups, elixirs, and concentrated drops.
  • Non toxic solid carriers or diluents may be used which include, for example, mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, glucose, sucrose, magnesium, carbonate, and the like.
  • binders which are agents which impart cohesive qualities to powdered materials are also necessary.
  • Disintegrants are also necessary in the tablets to facilitate break-up of the tablet. Disintegrants include starches, clays, celluloses, algins, gums and crosslinked polymers. Moreover, lubricants and glidants are also included in the tablets to prevent adhesion to the tablet material to surfaces in the manufacturing process and to improve the flow characteristics of the powder material during manufacture. Colloidal silicon dioxide is most commonly used as a glidant and compounds such as talc or stearic acids are most commonly used as lubricants.
  • the dietary supplement composition may comprise further ingredient providing beneficial effects to the subject such as vitamins (e.g. vitamin D), amino acids, proteins, lipids (omega 3 fatty acids), ursolic acid, tomaditine, antioxidants, polyphenols, isoflavones present in soybean and derivatives, tea leaves components and garlic compounds.
  • vitamins e.g. vitamin D
  • amino acids amino acids
  • proteins proteins
  • lipids miga 3 fatty acids
  • ursolic acid tomaditine
  • antioxidants e.g., polyphenols
  • isoflavones present in soybean and derivatives e.g., tea leaves components and garlic compounds.
  • the present invention also relates to the use of a compound of formula (I) as defined above, or any acceptable salt, hydrate, solvate or prodrug thereof, as ingredient for animal feed composition or as additive for animal feed composition. It also relates to the use of a compound of formula (I) as defined above, or any acceptable salt, hydrate, solvate or prodrug thereof, to prepare an ingredient or additive for animal feed composition. It further relates to an ingredient or additive for animal feed composition comprising a compound of formula (I) as defined above, or any acceptable salt, hydrate, solvate or prodrug thereof.
  • feed composition for livestock comprising a compound of formula (I) as defined above, or any acceptable salt, hydrate, solvate or prodrug thereof, as ingredient or additive.
  • the feed composition, ingredient, additive, or dietary supplement of the invention may further comprise any edible GRAS (generally recognized as safe) material such as, for example, corn gluten feed, sunflower hulls, distillers grains, guar hulls, wheat middlings, rice hulls, rice bran, oilseed meals, dried blood meal, animal by-product meal, fish by-product, fish meal, dried fish solubles, feather meal, poultry by-products, meat meal, bone meal, dried whey, soy protein concentrate, soy flour, yeast, wheat, oats, grain sorghums, corn feed meal, rye, corn, barley, aspirated grain fractions, brewers dried grains, corn flour, corn gluten meal, feeding oat meal, sorghum grain flour, wheat mill run, wheat red dog, hominy feed, wheat flour, wheat bran, wheat germ meal, oat groats, rye middlings, cotyledon fiber, ground grains, or a mixture thereof.
  • GRAS generally recognized as safe
  • the feed composition, ingredient, additive, or dietary supplement of the invention is used as non-therapeutic skeletal muscle hypertrophy inducer, and in particular to improve livestock performance, i.e. to increase liveweight gain.
  • the feed composition, ingredient, additive, or dietary supplement is intended to be administered to a healthy subject, i.e. a subject who is not suffering from a disease or disorder resulting in loss of skeletal muscle tissue and/or muscle weakness.
  • the subject may be as defined above for the dietary supplement composition of the invention.
  • the invention also relates to a method of improving livestock performance and/or health comprising providing to said livestock a compound of formula (I) as defined above, or any acceptable salt, hydrate, solvate or prodrug thereof, in particular a feed composition, ingredient, additive, or dietary supplement of the invention.
  • a feed composition for example, a feed composition, ingredient, additive, or dietary supplement of the invention.
  • the term "improving livestock performance” refers to increase liveweight gain.
  • This use is intended to be a non- therapeutic use as explained above and preferably, the compound, feed composition, ingredient, additive, or dietary supplement is intended to be administered to healthy livetstock, i.e. who is not suffering from a disease or disorder resulting in loss of skeletal muscle tissue and/or muscle weakness.
  • the feed composition, ingredient, additive, or dietary supplement may be in the form of a powder, liquid, or solid.
  • Ingredients of the feed composition of the invention other than the compound of formula (I) depend on the nature of the livestock and may be easily chosen by the skilled person.
  • the feed composition of the invention is in a form and/or a composition approved by a governmental institution such as National Food Administration (for example ANSES in France, ACIA in Canada, or FAD in the US).
  • a governmental institution such as National Food Administration (for example ANSES in France, ACIA in Canada, or FAD in the US).
  • Healthy donor primary skeletal cells Donor 1, Donor 3 and Donor 5
  • HSMM Human Skeletal Muscle Myoblasts
  • DMD Digienne muscular dystrophy
  • Muscle cells were maintained in culture following the supplier instructions with supplements and fetal bovine serum (FBS) serum provided by Lonza. An amplification step was performed in order to obtain enough cells for seeding the screening plates.
  • FBS fetal bovine serum
  • Hypertrophy and Atrophy Rescue assays were performed using an in vitro fully automated human myotube model called MyoScreenTM (Cytoo, France). This model relies on a tight control of the microenvironment that guides the differentiation of human primary myoblasts.
  • Myotubes formed on MyoScreenTM micropatterns present a high level of maturation together with a highly standardized morphology.
  • Human primary myoblasts from donors were seeded in MyoScreenTM micropatterned 96- well plates (Cytoo, France), let them adhere for 24h in growth medium, then run the differentiation in a low horse serum medium for at least 5 days.
  • the growth medium was changed for a differentiation medium, 300 ⁇ 1 ⁇ 11 (DMEM with 0.1% horse serum) in which myoblasts started differentiating and forming myotubes.
  • the differentiation medium was changed. Then candidate compounds were diluted with differentiation medium and transferred into the plate.
  • the final concentration of DMSO should be not higher than 0.1%.
  • At least 6 wells were treated with the vehicle as a basal control, and 6 wells were treated with IGF-1 at lOOng/ml as positive hypertrophy control.
  • Atrophy Rescue assay one hour after candidate compound addition, atrophy inducers were added at the following final concentration: 150 ng/mL of myostatin, 25 ng/mL of IL- ⁇ , 2 ng/mL of TNF-a, 0.5 ng/mL of TGF- ⁇ and ⁇ of dexamethasone.
  • Images were acquired at lOx magnification with an Operetta High Content Imaging System. Image processing and analysis were performed with dedicated algorithms developed on the Acapella High Content Imaging Software (Perkin Elmer) by CYTOO. Eleven fields per well were acquired.
  • segmentation of myotubes and nuclei were done using respectively the Troponin T staining intensity and the Hoechst staining.
  • One to two myotubes per micropattern were usually identified (a myotube is a troponin T staining area that includes at least 2 nuclei).
  • the threshold of segmentation was set-up in order to avoid detecting the background noise and eliminate aberrant small myotube structures.
  • specific readouts were calculated in the whole well, like the nuclei count and the fusion index (percentage of nuclei included in troponin T staining). Usually around 50 to 60 myotubes were detected per well in a control condition.
  • Nuclei Count, Fusion Index, Mean myotube Area and Number of nuclei per myotube have been validated as relevant and sensitive readouts of myotube differentiation as well as atrophic and hypertrophic induction.
  • Dose response assays were performed on Donor cells: 8 doses of candidate compounds between 33 ⁇ and 0.015 ⁇ , 2 well replicates per dose.
  • Atrophy Rescue assays were performed in the presence of atrophy inducers, i.e. TNF-a, IL- 1 ⁇ , Myostatin, TGF- ⁇ and dexamethasone. Each compound was tested in triplicate of wells at 1 ⁇ for AB-MECA and NECA.
  • adenosine receptor 3 (AB-MECA, IB-MECA and APNEA) and adenosine receptor 1 (N6-cyclohexyladenosine, GR 79236X, NECA and 2-phenylaminoadenosine) analogs.
  • the retest allowed ranking more precisely the activity of each compound compared to the other ones.
  • the most potent compounds from each sub-group were selected for further characterization (IB-MECA, APNEA, GR 79236X and NECA).
  • the compounds were active on both healthy male and female donors. Their EC 50 could not be defined precisely because the dose response range was too high to detect both minimum and maximum activity levels.
  • Atrophy rescue assays were performed for APNEA and NECA and results are presented in Table 5.
  • Myotubes from donor 3 cells were atrophied using different inducers: inflammation cytokines (IL- ⁇ , TNF-a), SMAD pathway activators (Myostatin, TGF- ⁇ ), and one glucocorticoid (dexamethasone).
  • inflammation cytokines IL- ⁇ , TNF-a
  • Myostatin Myostatin, TGF- ⁇
  • glucocorticoid diocorticoid
  • APNEA and NECA can inhibit the atrophy induced by IL- ⁇ , TNF- a, Myostatin, TGF- ⁇ and dexamethasone.

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Abstract

La présente invention concerne des inducteurs d'hypertrophie du muscle squelettique ainsi que leurs utilisations pour favoriser la régénération du muscle squelettique, pour prévenir l'atrophie musculaire squelettique, ou dans le traitement ou la prévention d'une maladie ou d'une lésion entraînant une perte de tissu musculaire squelettique et/ou une faiblesse musculaire. L'invention concerne en outre l'utilisation non thérapeutique de tels composés pour augmenter la masse musculaire, la force musculaire et/ou la performance musculaire chez un sujet.
PCT/EP2017/079669 2016-11-17 2017-11-17 Inducteurs d'hypertrophie du muscle squelettique Ceased WO2018091689A1 (fr)

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WO2020058072A1 (fr) * 2018-09-18 2020-03-26 Société des Produits Nestlé S.A. Composés inhibiteurs de src pour la modulation des muscles squelettiques, procédés et utilisations de ceux-ci
KR20210110055A (ko) 2020-02-28 2021-09-07 주식회사 종근당바이오 P1, p4-디(우리딘 5'-)테트라포스페이트 나트륨염 4 수화물 결정형 a의 제조방법
WO2024161042A1 (fr) * 2023-02-03 2024-08-08 Cytoo Dosages de colocalisation quantitative pour évaluer l'activité et l'efficacité de thérapies ciblant des troubles musculaires
EP4400103A4 (fr) * 2021-09-09 2025-08-20 Univ Kyushu Nat Univ Corp Procédé de prévention de la nitration de résidus tyrosine dans le facteur de croissance hépatocytaire à l?aide d?un composé trisulfure

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020058072A1 (fr) * 2018-09-18 2020-03-26 Société des Produits Nestlé S.A. Composés inhibiteurs de src pour la modulation des muscles squelettiques, procédés et utilisations de ceux-ci
KR20210110055A (ko) 2020-02-28 2021-09-07 주식회사 종근당바이오 P1, p4-디(우리딘 5'-)테트라포스페이트 나트륨염 4 수화물 결정형 a의 제조방법
EP4400103A4 (fr) * 2021-09-09 2025-08-20 Univ Kyushu Nat Univ Corp Procédé de prévention de la nitration de résidus tyrosine dans le facteur de croissance hépatocytaire à l?aide d?un composé trisulfure
WO2024161042A1 (fr) * 2023-02-03 2024-08-08 Cytoo Dosages de colocalisation quantitative pour évaluer l'activité et l'efficacité de thérapies ciblant des troubles musculaires

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