Phenoxy acetic acids and phenyl propionic acids as PPAR delta agonists
Phenoxy acetic acids and phenyl propionic acids and their use in improving mitochondrial energy output in a subject are provided herein. The present compounds are activators of PPARδ and may be useful for treating conditions mediated by the same.
1. A method of improving mitochondrial energy output in a subject, the method comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof:
wherein is a double bond, with either E or Z substitution;
X 1 is C 1-6 alkyl substituted with morpholino;
X 2 is phenylene;
X 3 is phenyl substituted with one or more halogens;
Ar is phenylene optionally substituted with methyl;
Y 1 is O;
Y 2 is CH 2 ;
Z is CH 2 ;
R 1 is hydrogen; and
R 2 is hydrogen.
2. The method of claim 1 , wherein X 1 is morpholin-4-ylmethyl.
3. The method of claim 1 , wherein the compound is (E)-[4-[3-(4-Chlorophenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methylphenyl]-propionic acid or a pharmaceutically acceptable salt thereof.
4. The method of claim 1 , wherein the compound is (Z)-[4-[3-(4-Chlorophenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methylphenyl]-propionic acid or a pharmaceutically acceptable salt thereof.
5. A method of improving mitochondrial energy output in a subject, the method comprising administering to a subject in need thereof an effective amount of a compound of selected from the group consisting of:
(Z)-[2-Methyl-4-[3-(4-methylphenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-phenoxy]acetic acid;
(E)-[2-Methyl-4-[3-[4-[3-(pyrazol-1-yl)prop-1-ynyl]phenyl]-3-(4-trifluoromethylphenyl)-allyloxy]phenoxy]acetic acid;
(E)-[2-Methyl-4-[3-[4-[3-(morpholin-4-yl)propynyl]phenyl]-3-(4-trifluoromethylphenyl) allyloxy]-phenoxy]acetic acid;
(E)-[2-Methyl-4-[3-(4-methylphenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-phenoxy]acetic acid; and
(Z)-[2-Methyl-4-[3-[4-[3-(morpholin-4-yl)propynyl]phenyl]-3-(4-trifluoromethylphenyl) allyloxy]-phenoxy]acetic acid;
or a pharmaceutically acceptable salt thereof.
6. The method of claim 5 , wherein the compound is (Z)-[2-Methyl-4-[3-(4-methylphenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-phenoxy]acetic acid or a pharmaceutically acceptable salt thereof.
7. The method of claim 5 , wherein the compound is (E)-[2-Methyl-4-[3-[4-[3-(pyrazol-1-yl)prop-1-ynyl]phenyl]-3-(4-trifluoromethylphenyl)-allyloxy]phenoxy]acetic acid or a pharmaceutically acceptable salt thereof.
8. The method of claim 5 , wherein the compound is (E)-[2-Methyl-4-[3-[4-[3-(morpholin-4-yl)propynyl]phenyl]-3-(4-trifluoromethylphenyl)allyloxy]-phenoxy]acetic acid or a pharmaceutically acceptable salt thereof.
9. The method of claim 5 , wherein the compound is (E)-[2-Methyl-4-[3-(4-methylphenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-phenoxy]acetic acid or a pharmaceutically acceptable salt thereof.
10. The method of claim 5 , wherein the compound is (Z)-[2-Methyl-4-[3-[4-[3-(morpholin-4-yl)propynyl]phenyl]-3-(4-trifluoromethylphenyl) allyloxy]-phenoxy]acetic acid or a pharmaceutically acceptable salt thereof.