PPAR agonists
Provided herein are compounds and compositions useful in increasing PPARδ activity. The compounds and compositions provided herein are useful for the treatment of PPARδ related diseases (e.g., muscular diseases, vascular disease, demyelinating disease, and metabolic diseases).
1. A method, comprising contacting a PPARδ protein with an effective amount of one or more compounds having a formula
or a salt thereof, wherein:
Z is R 1 L 1 C(O)—, or a carboxyl bioisostere;
R 1 is hydrogen, aliphatic, —OR 1A , —NR 1A R 1B , —C(O)R 1A , —S(O) 2 R 1A , —C(O)OR 1A , —S(O) 2 NR 1A R 1B or —C(O)NR 1A R 1B ;
each of R 1A , R 1B R 3A and R 3B independently is hydrogen or aliphatic;
L 1 is a bond or —NR 30 —, where R 30 is H;
L 2 is a bond, C 4-7 aliphatic, heteroaliphatic, arylene, heteroarylene, cycloalkylene, or heterocycloalkylene;
X is O;
ring A is phenyl;
ring B is selected from phenyl, pyridine, thiophene, thiazole, pyrazole, oxazole, isoxazole, benzo[b]furan, indazole, piperidine, cyclohexane, piperidin-2-one, piperazine-2,5-dione or quinazolin-4(3H)-one;
each R 2 independently is halogen, aryl, heteroaryl, aliphatic, heteroaliphatic, cyano, NO 2 , OH, or amino or two adjacent R 2 groups form a fused ring system with ring B;
L 3 ′ is —C(O)—;
L 3 is a bond or aliphatic;
L 4 is selected from a bond, aliphatic, heteroaliphatic, arylene, heteroarylene, cycloalkylene, or heterocycloalkylene;
R 3 is selected from —OH, —OR 3A , —NR 3A R 3B , —C(O)R 3A , —S(O) 2 R 3A , —C(O)OR 3A , —S(O) 2 NR 3A R 3B , or —C(O)NR 3A R 3B , aliphatic, heteroaliphatic, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R 22 independently is selected from halogen, aryl, heteroaryl, aliphatic, heteroaliphatic, cyano, NO 2 , OH, or amino;
n is from 1 to 5; and
m is from 0 to 4;
with the provisos that
if -L 3 N(L 4 R 3 )L 3 - is —CH 2 N(L 4 R 3 )C(O)—, L 4 R 3 is n-propyl or isopropyl, and n is 1 then R 2 is not 4-bromo or 4-benzo[d][1,3]dioxole;
and where the compound is not
ethyl 6-(2-((4-bromo-N-propylbenzamido)methyl)phenoxy)hexanoate;
ethyl 6-(2-((4-(benzo[d][1,3]dioxol-5-yl)-N-propylbenzamido)methyl)phenoxy)hexanoate;
6-(2-((4-(benzo[d][1,3]dioxol-5-yl)-N-propylbenzamido)methyl)phenoxy)hexanoic acid;
ethyl 6-(2-((4-(benzo[d][1,3]dioxol-5-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoate;
6-(2-((4-(benzo[d][1,3]dioxol-5-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoic acid.
2. The method of claim 1 , wherein the carboxyl bioisostere is selected from
and
X 7 , Y 7 , and Z 7 are each independently selected from N, CH 2 or CO;
X 8 is selected from O, S or NMe; and
X 9 is selected from O, N, NH, S, CH or CH 2 .
3. The method of claim 1 , wherein the compound has a formula selected from:
4. The method of claim 1 , wherein R 3 is selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl.
5. The method of claim 1 , wherein L 3 and L 4 are each independently selected from a bond or alkylene.
6. The method of claim 1 , wherein L 4 R 3 is isopropyl, cyclopropyl, cyclopentyl, sec-butyl, benzyl, morpholinopropyl, or (2-pyridinyl)ethyl.
7. The method of claim 1 , wherein each R 2 independently is Cl, F, I, Br, cyano, NO 2 , or OH.
8. The method of claim 1 , wherein each R 2 independently is halogen, alkyloxy, haloalkyloxy, cycloalkyloxy, haloalkyl, alkyl, amino, heterocyclic, aryl, cycloaliphatic or heteroaryl.
9. The method of claim 7 , wherein n is from 2 to 4, and two adjacent R 2 groups form a fused ring system with ring B.
10. The method of claim 1 , wherein at least one R 2 is para to L 3 ′ and is selected from bromo, phenyl, 3-pyridinyl, 4-pyridinyl, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 4-ethylphenyl, 2-ethylphenyl, 2,3-dimethylphenyl, 2,5-dimethylphenyl, 3,5-dimethylphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, (1,1′-biphenyl)-2-yl, or
11. The method of claim 1 , wherein n is 1 and R 2 is furan-2-yl or furan-3-yl.
12. The method of claim 1 , wherein L 2 is
13. The method of claim 1 , wherein L 2 is C 1-6 linear or branched alkylene.
14. The method of claim 1 , wherein L 2 is a bond or C 4-7 alkylene.
15. The method of claim 1 , wherein the PPARδ protein is present in a subject, and contacting comprises administering an effective amount of the one or more compounds to the subject.
16. The method of claim 15 , wherein contacting the PPARδ protein within the subject increases or maintains muscle mass or muscle tone in the subject.
17. The method of claim 15 , wherein the compound is administered to the subject to provide a dose of at least one compound in a therapeutically effective amount of from about 1 mg/kg to about 10 mg/kg.
18. The method of claim 15 , wherein administering the one or more compounds comprises treating a PPARδ related disease or condition selected from a vascular disease, muscular disease, demyelinating disease, or a metabolic disease.