title: Design and synthesis of heterocyclic malonyl-CoA decarboxylase inhibitors.
abstract: 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.
authors.affiliation: Department of Chemistry, Chugai Pharma USA, LLC, 6275 Nancy Ridge Drive, San Diego, CA 92121, USA. jcheng@trlusa.com
authors.forename: Jie-Fei
authors.initials: JF
authors.lastname: Cheng
authors.forename: Mi
authors.initials: M
authors.lastname: Chen
authors.forename: Bin
authors.initials: B
authors.lastname: Liu
authors.forename: Zheng
authors.initials: Z
authors.lastname: Hou
authors.forename: Thomas
authors.initials: T
authors.lastname: Arrhenius
authors.forename: Alex M
authors.initials: AM
authors.lastname: Nadzan
mesh_terms: D000818:Animals; D002262:Carboxy-Lyases / Q000037:antagonists & inhibitors*; D002316:Cardiotonic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D015195:Drug Design; D004734:Energy Metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D007093:Imidazoles / Q000737:chemistry; D008956:Models, Chemical; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D013552:Swine
chemical_list: D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D005227:Fatty Acids; D007093:Imidazoles; C029899:imidazole; D002262:Carboxy-Lyases; C021532:malonyl-CoA decarboxylase; D005947:Glucose