methyl-5-(n-(4-(1-1-1-3-3-3-hexafluoro-2-hydroxypropan-2-yl)phenyl)morpholine-4-carboxamido)pentanoate and Myocardial-Ischemia

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.

Topics: Animals; Carboxy-Lyases; Energy Metabolism; Fatty Acids; Glucose; In Vitro Techniques; Male; Malonyl Coenzyme A; Morpholines; Myocardial Ischemia; Myocardium; Oxidation-Reduction; Phenylurea Compounds; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Swine