Use of a ppar-delta agonist for reducing loss of muscle strength, muscle mass, or type i muscle fibers in an immobilized limb

Abstract

The present invention provides methods for reducing loss of muscle strength, muscle mass, or Type I muscle fibers in an immobilized limb by administering (E)-[4-[3-(4-Fluorophenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetic acid or a pharmaceutically acceptable salt thereof.

1 . A method of treating muscle atrophy in a subject comprising administering to the subject in need thereof a small molecule PPARδ agonist, wherein the PPARδ agonist: has a molecular weight of less than 1000 g/mol; an EC50 value of less than 500 nM as determined by a PPARδ transient transactivation assay; and at least a 10-fold potency for activation of PPARδ relative to either or both of PPARα and PPARγ. 
     
     
         2 . The method of  claim 1 , wherein the small molecule PPARδ agonist: increases muscle mass in the subject; modulates muscle growth, enhances muscle formation, increases muscle strength, maintains muscle strength or reduces loss of muscle strength in the subject; or reducing the rate of decrease in mitochondrial biogenesis in a muscle tissue; or combination thereof. 
     
     
         3 . A method of modulating muscle in a subject with muscle atrophy comprising administering to the subject in need thereof a selective PPARδ agonist, wherein the muscle modulation is selected from: increasing muscle mass in the subject; modulating muscle growth, enhancing muscle formation, increasing muscle strength, maintaining muscle strength or reducing loss of muscle strength in the subject; or reducing the rate of decrease in mitochondrial biogenesis in a muscle tissue; or combination thereof; and wherein the selective PPARδ agonist is characterized by at least a 10-fold potency for activation of PPARδ relative to either or both of PPARα and PPARγ. 
     
     
         4 . The method of  claim 3 , wherein the small molecule PPARδ agonist reduces the rate of loss of Type I muscle fibers. 
     
     
         5 . The method of  claim 1 , wherein the treatment comprises activating PPARδ in skeletal muscle in the subject. 
     
     
         6 . The method of  claim 1 , wherein the muscle atrophy is skeletal muscle atrophy secondary to a chronic disease. 
     
     
         7 . The method of  claim 6 , wherein the chronic disease is a neurologic disease or drug-induced muscle disease. 
     
     
         8 . The method of  claim 6 , wherein the chronic disease is multiple sclerosis, amyotrophic lateral sclerosis, spinal muscular atrophy, critical illness neuropathy, cancer, congestive heart failure, chronic pulmonary disease, chronic renal failure, chronic liver disease, diabetes mellitus, Cushing syndrome, chronic infection, glucocorticoid-induced myopathy, statin-induced myopathy, polymyositis or dermatomyositis. 
     
     
         9 . The method of  claim 1 , wherein the muscle atrophy is skeletal muscle atrophy secondary to a genetic disease that primarily affect skeletal muscle. 
     
     
         10 . (canceled) 
     
     
         11 . The method of  claim 1 , wherein the muscle atrophy is disease-associated muscle atrophy. 
     
     
         12 . The method of  claim 11 , wherein the disease-associated muscle atrophy results from a muscle disease. 
     
     
         13 . (canceled) 
     
     
         14 . The method of  claim 12 , wherein the muscle disease occurs as a response to a systemic illness; and wherein the systemic illness is hypothyroidism, hyperthyroidism, adrenal gland depletion, diabetes mellitus, or an autoimmune disease; or wherein the systemic illness is cancer, Acquired Immune Deficiency Syndrome (AIDS), chronic obstructive lung disease, congestive heart failure, cardiomyopathy, chronic liver disease, renal disease, emphysema, tuberculosis, osteomalacia, hormonal deficiency, anorexia nervosa, and or generalized malnutrition. 
     
     
         15 - 27 . (canceled) 
     
     
         28 . The method of  claim 1 , wherein the PPARδ agonist is (E)-[4-[3-(4-fluorophenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetic acid or a pharmaceutically acceptable salt thereof. 
     
     
         29 . (canceled) 
     
     
         30 . A method of treating muscle atrophy in a human comprising administering to the human in need thereof the compound (E)-[4-[3-(4-fluorophenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetic acid, or a pharmaceutically acceptable salt thereof, wherein the muscle atrophy is disuse-associated muscle atrophy, disease-associated muscle atrophy, or drug-induced muscle atrophy. 
     
     
         31 . The method of  claim 30 , wherein the muscle atrophy is disease-associated muscle atrophy; wherein disease-associated muscle atrophy comprises muscle atrophy as a secondary consequence of advanced cancer, Acquired Immune Deficiency Syndrome (AIDS), chronic obstructive lung disease, congestive heart failure, cardiomyopathy, chronic liver disease, renal disease, emphysema, tuberculosis, osteomalacia, hormonal deficiency, anorexia nervosa, generalized malnutrition and drug abuse. 
     
     
         32 . The method of  claim 30 , wherein the muscle atrophy is skeletal muscle atrophy secondary to malnutrition, muscle disuse, neurologic disease, orthopedic injury, casting and other post-surgical forms of limb immobilization, chronic disease, burns, sepsis, other illnesses requiring mechanical ventilation, drug-induced muscle disease, autoimmune diseases that affect skeletal muscle, spaceflight, periods of exposure to zero or low gravity, bed rest, corticosteroid use, denervation, chronic renal failure, neuromuscular disorders, age-related sarcopenia, or arthritis. 
     
     
         33 . The method of  claim 32 , wherein the neurological disease is multiple sclerosis, amyotrophic lateral sclerosis, spinal muscular atrophy, critical illness neuropathy, spinal cord injury or peripheral nerve injury. 
     
     
         34 . The method of  claim 30 , wherein the muscle atrophy is skeletal muscle atrophy that is associated with bed rest, corticosteroid use, denervation, chronic renal failure, limb immobilization, neuromuscular disorders, sarcopenia of aging, or arthritis. 
     
     
         35 . The method of  claim 34 , wherein the sarcopenia is characterized by loss of muscle mass and function. 
     
     
         36 . The method of  claim 30 , wherein: (E)-[4-[3-(4-fluorophenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetic acid or a pharmaceutically acceptable salt thereof is administered at a dose of 50-200 mg per day.