Modulation of estrogen receptor-related receptor gamma (ERRγ) and uses therefor
This application provides methods of increasing vascularization, muscle performance, muscle rehabilitation, and/or mitochondrial activity in subjects in need thereof, by administering a therapeutically effective amount of one or more agents that increases ERRγ activity to the subject. Such agents can include one or more ERRγ agonists. In some examples the method does not require that the subject exercise, and as such, the subject may be sedentary (such as bedridden or in a wheelchair).
1. A method of increasing vascularization in a mammal's skeletal muscle, comprising:
administering a therapeutically effective amount of one or more agents that increases estrogen-related receptor gamma (ERRγ) activity to a mammal, wherein the one or more agents that increases ERRγ activity is
wherein R is H (DY162), p-CH 3 (DY163), 2-Cl, 3-CF 3 (DY165), p-CF 3 (DY168), p-OCH 3 (DY169), 3-NO 2 , 4CF 3 (DY170), 2,3-O 2 CH 3 (DY174), or m-CH 3 (DY159),
wherein X is S and R is 5-CH 3 (DY166), 5-CH 2 CH 3 (DY164), or 5-NO 2 (DY167);
wherein X is O and R is 4,5-CH 3 (DY173) or CH 2 CH 3 (DY175), or wherein X is CH, and R is 2-C1, 3-CF 3 , p-CF 3 ; p-OCH 3 , 3-NO 2 , 4-CF 3 ; or 2,3-O 2 CH 3 ;
wherein R is H (DY117) or R is Br (DY172),
wherein
m is 0, 1 or 2;
n is 0, 1 or 2;
R 1 and R 7 are independently selected from
1) H;
2) Halo;
3) OH;
4) (C=0) a ,O b C 1 -C 4 alkyl, wherein a is 0 or 1 and b is 0 or 1, wherein the alkyl can be substituted by 0, 1 or more substituted groups independently selected from H or C 3 C 6 heterocyclyl;
5) (C=0), O b C 3 -C 6 cycloalkyl, wherein a is 0 or 1 and b is 0 or 1;
R2 is selected from:
1) H;
2) C 1 -C 3 alkyl, wherein the alkyl can be substituted by 0, 1 or more substituted groups independently selected from H or C 3 C 6 heterocyclyl;
3) C 3 -C 6 cycloalkyl;
or combinations thereof; and
not exercising the mammal, wherein the mammal has muscle atrophy due to sarcopenia, cachexia, being bedridden, being confined to a wheelchair, having had a limb in a cast, cancer, AIDS, congestive heart failure, chronic obstructive pulmonary disease, renal failure, a severe burn, Dejerine Sottas syndrome (HSMN Type III), weightlessness, liver failure, starvation, disuse, or muscular dystrophy.
2. The method of claim 1 , wherein the method further comprises:
selecting the mammal having muscle atrophy due to sarcopenia, cachexia, being bedridden, being confined to a wheelchair, having had a limb in a cast, cancer, AIDS, congestive heart failure, chronic obstructive pulmonary disease, renal failure, a severe burn, Dejerine Sottas syndrome (HSMN Type III), weightlessness, liver failure, starvation, disuse, or muscular dystrophy.
3. The method of claim 1 , wherein the mammal is a human.
4. The method of claim 1 , wherein the ERRγ agonist is DY131, GSK4716, or combinations thereof.
5. A method of increasing vascularization in a mammal's skeletal muscle by at least 25%, comprising:
administering a therapeutically effective amount of one or more agents that increases ERRγ activity to a mammal, wherein the one or more agents that increases ERRγ activity is
wherein R is H (DY162), p-CH 3 (DY163), 2-Cl, 3-CF 3 (DY165), p-CF 3 (DY168), p-OCH 3 (DY169), 3-NO 2 , 4CF 3 (DY170), 2,3-O 2 CH 3 (DY174), or m-CH 3 (DY159),
wherein X is S and R is 5-CH 3 (DY166), 5-CH 2 CH 3 (DY164), or 5-NO 2 (DY167);
wherein X is O and R is 4,5-CH 3 (DY173) or CH 2 CH 3 (DY175), or wherein X is CH, and R is 2-C1, 3-CF 3 , p-CF 3 ; p-OCH 3 , 3-NO 2 , 4-CF 3 ; or 2,3-O 2 CH 3 ;
wherein R is H (DY117) or R is Br (DY172),
wherein
m is 0, 1 or 2;
n is 0, 1 or 2;
R 1 and R 7 are independently selected from
1) H;
2) Halo;
3) OH;
4) (C=0) a ,O b C 1 C 4 alkyl, wherein a is 0 or 1 and b is 0 or 1, wherein the alkyl can be substituted by 0, 1 or more substituted groups independently selected from H or C 3 C 6 heterocyclyl;
5) (C=0), O b C 3 -C 6 cycloalkyl, wherein a is 0 or 1 and b is 0 or 1;
R2 is selected from:
1) H;
2) C 1 -C 3 alkyl, wherein the alkyl can be substituted by 0, 1 or more substituted groups independently selected from H or C 3 C 6 heterocyclyl;
3) C 3 -C 6 cycloalkyl;
or combinations thereof; and
not exercising the mammal,
wherein the mammal has muscle atrophy due to sarcopenia, cachexia, is bedridden, is confined to a wheelchair, had a limb in a cast, cancer, AIDS, congestive heart failure, chronic obstructive pulmonary disease, renal failure, a severe burn, Dejerine Sottas syndrome (HSMN Type III), weightlessness, liver failure, starvation, disuse, or muscular dystrophy, and
wherein the increase of at least 25% is relative to an amount of vascularization in the absence of administration of the one or more agents that increases ERRγ activity.
6. A method of enhancing muscle rehabilitation or muscle performance in a mammal, comprising:
administering a therapeutically effective amount of one or more agents that increases ERRγ activity to a mammal, wherein the one or more agents that increases ERRγ activity is
wherein R is H (DY162), p-CH 3 (DY163), 2-Cl, 3-CF 3 (DY165), p-CF 3 (DY168), p-OCH 3 (DY169), 3-NO 2 , 4CF 3 (DY170), 2,3-O 2 CH 3 (DY174), or m-CH 3 (DY159),
wherein X is S and R is 5-CH 3 (DY166), 5-CH 2 CH 3 (DY164), or 5-NO 2 (DY167);
wherein X is O and R is 4,5-CH 3 (DY173) or CH 2 CH 3 (DY175), or whereinX is CH, and R is 2-C1, 3-CF 3 p-CF 3 ; p-OCH 3 , 3-NO 2 , 4-CF 3 ; or 2,3-O 2 CH 3 ;
wherein R is H (DY117) or R is Br (DY172),
wherein
m is 0, 1 or 2;
n is 0, 1 or 2;
R 1 and R 7 are independently selected from
1) H;
2) Halo;
3) OH;
4) (C=0) a ,O b C 1 C 4 alkyl, wherein a is 0 or 1 and b is 0 or 1, wherein the alkyl can be substituted by 0, 1 or more substituted groups independently selected from H or C 3 C 6 heterocyclyl;
5) (C=0), O b C 3 -C 6 cycloalkyl, wherein a is 0 or 1 and b is 0 or 1;
R 2 is selected from:
1) H;
2) C 1 -C 3 alkyl, wherein the alkyl can be substituted by 0, 1 or more substituted groups independently selected from H or C 3 C 6 heterocyclyl;
3) C 3 -C 6 cycloalkyl;
or combinations thereof; and
not exercising the mammal,
wherein the mammal has muscle atrophy due to sarcopenia, cachexia, is bedridden, is confined to a wheelchair, had a limb in a cast, cancer, AIDS, congestive heart failure, chronic obstructive pulmonary disease, renal failure, a severe burn, Dejerine Sottas syndrome (HSMN Type III), weightlessness, liver failure, starvation, disuse, or muscular dystrophy, and
wherein muscle rehabilitation or muscle performance is enhanced when running endurance of the muscle is increased as measured by a treadmill test, creatine kinase level is increased in the blood, electrical activity in the muscle is increased as measured by electromyography, or elasticity of the muscle is increased as measured by elastography.
7. A method of enhancing muscle rehabilitation or muscle performance in a mammal by at least 25%, comprising:
administering a therapeutically effective amount of one or more agents that increases ERRγ activity to a mammal, wherein the one or more agents that increases ERRγ activity is
wherein R is H (DY162), p-CH 3 (DY163), 3-CF 3 (DY165), p-CF 3 (DY168), p-OCH 3 (DY169), 3-NO 2 , 4CF 3 (DY170), 2,3-O 2 CH 3 (DY174), or m-CH 3 (DY159),
swherein X is S and R is 5-CH 3 (DY166), 5-CH 2 CH 3 (DY164), or 5-NO 2 (DY167); wherein X is O and R is 4,5-CH 3 (DY173) or CH 2 CH 3 (DY175), or wherein X is CH, and R is 2-C1, 3-CF 3 , p-CF 3 ; p-OCH 3 , 3-NO 2 , 4-CF 3 ; or 2,3-O 2 CH 3 ;
wherein R is H (DY117) or R is Br (DY172),
wherein
m is 0, 1 or 2;
n is 0, 1 or 2;
R 1 and R 7 are independently selected from
1) H;
2) Halo;
3) OH;
4) (C=0) a , O b C 1 -C 4 alkyl, wherein a is 0 or 1 and b is 0 or 1, wherein the alkyl can be substituted by 0, 1 or more substituted groups independently selected from H or C 3 -C 6 heterocyclyl;
5) (C=0), O b C 3 -C 6 cycloalkyl, wherein a is 0 or 1 and b is 0 or 1;
R2 is selected from:
1) H;
2) C 1 -C 3 alkyl, wherein the alkyl can be substituted by 0, 1 or more substituted groups independently selected from H or C 3 C 6 heterocyclyl;
3) C 3 -C 6 cycloalkyl;
or combinations thereof; and
not exercising the mammal,
wherein the mammal has muscle atrophy due to sarcopenia, cachexia, is bedridden, is confined to a wheelchair, had a limb in a cast, cancer, AIDS, congestive heart failure, chronic obstructive pulmonary disease, renal failure, a severe burn, Dejerine Sottas syndrome (HSMN Type III), weightlessness, liver failure, starvation, disuse, or muscular dystrophy,
wherein muscle performance is enhanced when running endurance of the muscle is increased by at least 25% as measured by a treadmill test, creatine kinase level is increased in the blood by at least 25%, electrical activity in the muscle is increased by at least 25% as measured by electromyography, or elasticity of the muscle is increased by at least 25% as measured by elastography, and
wherein the increase of at least 25% is relative to an amount of muscle performance in the absence of administration of the one or more agents that increases ERRγ activity.
8. The method of claim 1 , wherein the mammal is a human that has muscular dystrophy.
9. The method of claim 1 , wherein the mammal is a human having muscle atrophy due to sarcopenia.
10. The method of claim 1 , wherein the mammal is a human having muscle atrophy due to being bedridden or being confined to a wheelchair.
11. The method of claim 1 , wherein the mammal is a human that has AIDS.
12. The method of claim 1 , wherein the mammal is a human that has congestive heart failure.
13. The method of claim 1 , wherein the mammal is a human that has chronic obstructive pulmonary disease.
14. The method of claim 1 , wherein the mammal is a human that has renal failure.
15. The method of claim 1 , wherein the mammal is a human that has liver failure.
16. The method of claim 1 , wherein the mammal is a human that has muscle atrophy due to experiencing a period of weightlessness.
17. The method of claim 1 , wherein the mammal is a human that has muscle atrophy due to disuse.
18. The method of claim 1 , wherein the one or more agents that increases ERRγ activity is: