Discovery of potent and orally available malonyl-CoA decarboxylase inhibitors as cardioprotective agents

  • J Med Chem. 2006 Jul 13;49(14):4055-8. doi: 10.1021/jm0605029.
Jie-Fei Cheng  1 ,  Yujin Huang ,  Richard Penuliar ,  Masahiro Nishimoto ,  Larry Liu ,  Thomas Arrhenius ,  Guang Yang ,  Eoin O'leary ,  Miguel Barbosa ,  Rick Barr ,  Jason R B Dyck ,  Gary D Lopaschuk ,  Alex M Nadzan
Affiliations
  • 1. Department of Chemistry, Chugai Pharma USA, LLC., 6275 Nancy Ridge Drive, San Diego, California 92121, USA. [email protected]
PMID: 16821767 DOI: 10.1021/jm0605029
Abstract

Discovery of 5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-4,5-dihydroisoxazole-3-carboxamides as a new class of malonyl-coenzyme A decarboxylase (MCD) inhibitors is described. tert-Butyl 3-(5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-4,5-dihydroisoxazole-3-carboxamido)butanoate (5, CBM-301940) exhibited excellent potency and in vivo PK/ADME properties. It is the most powerful stimulant of glucose oxidation reported to date in isolated working rat hearts. Compound 5 improved the cardiac efficiency and function in a rat heart global ischemia/reperfusion model, suggesting MCD inhibitors may be useful for the treatment of ischemic heart diseases.

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