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.
Cheng
Jie-Fei
JF
Department of Chemistry, Chugai Pharma USA, LLC, 6275 Nancy Ridge Drive, San Diego, CA 92121, USA. jcheng@trlusa.com
Chen
Mi
M
Liu
Bin
B
Hou
Zheng
Z
Arrhenius
Thomas
T
Nadzan
Alex M
AM
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
D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D005227:Fatty Acids; D007093:Imidazoles; C029899:imidazole; D002262:Carboxy-Lyases; C021532:malonyl-CoA decarboxylase; D005947:Glucose