Novel Pyrrole Inhibitors of S-Nitrosoglutathione Reductase as Therapeutic Agents for Liver Toxicity

1 . A method of treatment of liver toxicity which comprises administering a therapeutically effective amount of a GSNOR inhibitor of formula I to a patient in need thereof:

wherein:

Ar is selected from the group consisting of phenyl and thiophen-yl;

R 1 is selected from the group consisting of unsubstituted imidazolyl, substituted imidazolyl, chloro, bromo, fluoro, hydroxy, and methoxy;

R 2 is selected from the group consisting of hydrogen, methyl, chloro, fluoro, hydroxy, methoxy, ethoxy, propoxy, carbamoyl, dimethylamino, amino, formamido, and trifluoromethyl; and

X is selected from the group consisting of CO and SO 2 .

2 . The method of claim 1 wherein R 1 is selected from the group consisting of unsubstituted imidazolyl and substituted imidazolyl.

3 . The method of claim 2 wherein the substituted imidazolyl group is substituted with C 1 -C 6 alkyl.

4 . The method of claim 2 wherein ArR 1 R 2 is selected from the group consisting of:

wherein R 3 is selected from H, methyl, and ethyl.

5 . The method of claim 1 wherein the liver toxicity is acute liver toxicity.

6 . The method of claim 5 , wherein the acute liver toxicity is induced by acetaminophen.

7 . A method of treatment of liver toxicity which comprises administering a therapeutically effective amount of a GSNOR inhibitor of formula II to a patient in need thereof:

wherein:

Ar is selected from the group consisting of phenyl and thiophen-yl;

R 4 is selected from the group consisting of unsubstituted imidazolyl and substituted imidazolyl;

R 5 is selected from the group consisting of hydrogen, fluoro, hydroxy, and methoxy;

R 6 is selected from the group consisting of hydrogen, chloro, bromo, and fluoro;

R 7 is selected from the group consisting of hydrogen, and methyl; and

R 8 is selected from the group consisting of CONH 2 , SO 2 NH 2 , and NHSO 2 CH 3 .

8 . The method of claim 7 wherein the substituted imidazolyl group is substituted with C 1 -C 6 alkyl.

9 . The method of claim 7 wherein ArR 4 R 5 is selected from the group consisting of:

wherein R 9 , is selected from H, methyl, and ethyl.

10 . The method of claim 7 wherein the liver toxicity is acute liver toxicity.

11 . The method of claim 10 , wherein the acute liver toxicity is induced by acetaminophen.

12 . A method of inducing liver regeneration of lost or injured tissue comprising administering to a patient a therapeutically effective amount of a GSNOR inhibitor.

13 . A method of treating nonalcoholic steatohepatitis (NASH)-induced liver disease comprising administering to a patient a therapeutically effective amount of a GSNOR inhibitor.

14 . A method of treating liver failure comprising administering to a patient a therapeutically effective amount of a GSNOR inhibitor.