Synthesis and structure-activity relationship of small-molecule malonyl coenzyme A decarboxylase inhibitors

Journal of Medicinal Chemistry
Jie-Fei ChengAlex M Nadzan

Abstract

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.

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Citations

Dec 1, 2006·Cardiovascular Drugs and Therapy·Gary D Lopaschuk, William C Stanley
Aug 13, 2011·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Wan NamkungA S Verkman
Mar 8, 2007·Nutrition & Metabolism·Zahra Fatehi-Hassanabad, Catherine B Chan
Dec 1, 2015·International Journal of Cardiology·Yuri M LopatinPiotr Ponikowski
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Nov 1, 2005·Bioorganic & Medicinal Chemistry Letters·Jie-Fei ChengAlex M Nadzan
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May 20, 2008·Journal of Computational Chemistry·Jiazhong LiPaola Gramatica
Oct 18, 2012·American Journal of Physiology. Endocrinology and Metabolism·Victor SamokhvalovGary D Lopaschuk
Apr 29, 2006·Bioorganic & Medicinal Chemistry Letters·Jie-Fei ChengAlex M Nadzan
Jan 20, 2007·Bioorganic & Medicinal Chemistry Letters·David M WallaceAlex M Nadzan

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