Document Report Card

ID: ALA1138176

Journal: J Med Chem

Title: Synthesis and structure-activity relationship of small-molecule malonyl coenzyme A decarboxylase inhibitors.

Authors: Cheng JF, Chen M, Wallace D, Tith S, Haramura M, Liu B, Mak CC, Arrhenius T, Reily S, Brown S, Thorn V, Harmon C, Barr R, Dyck JR, Lopaschuk GD, Nadzan AM.

Abstract: The discovery and structure-activity relationship of first-generation small-molecule malonyl-CoA decarboxylase (MCD; CoA = coenzyme A) inhibitors are reported. We demonstrated that MCD inhibitors increased malonyl-CoA concentration in the isolated working rat hearts. Malonyl-CoA is a potent, endogenous, and allosteric inhibitor of carnitine palmitoyltransferase-I (CPT-I), a key enzyme for mitochondrial fatty acid oxidation. As a result of the increase in malonyl-CoA levels, fatty acid oxidation rates were decreased and the glucose oxidation rates were significantly increased. Demonstration of in vivo efficacy of methyl 5-(N-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)morpholine-4-carboxamido)pentanoate (6u) in a pig ischemia model indicated that MCD inhibitors may be useful for treating ischemic heart diseases.

CiteXplore: 16509570

DOI: 10.1021/jm050109n