Design and synthesis of heterocyclic malonyl-CoA decarboxylase inhibitors

We have previously reported the discovery of small molecule inhibitors of malonyl-CoA decarboxylase (MCD) as novel metabolic modulators, which inhibited fatty acid oxidation and consequently increased the glucose oxidation rates in the isolated working rat hearts. MCD inhibitors were also shown to improve cardiac efficiency in rat and pig demand-induced ischemic models through the mechanism-based modulation of energy metabolism. Herein, we describe the design and synthesis of a series of novel heterocyclic MCD inhibitors with a preference for substituted imidazole and isoxazole.

Graphical abstractBased on the initial HTS hit 1a, a series of heterocycles (1c) such as isoxazole and imidazoles designed to mimic the amide conformation was synthesized and SAR studies werre performed.Figure optionsDownload full-size imageDownload as PowerPoint slide