Synthesis and Structure−Activity Relationship of Small-Molecule Malonyl Coenzyme A Decarboxylase Inhibitors

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, endogen...

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Bibliographic Details
Published in:	Journal of medicinal chemistry Vol. 49; no. 5; pp. 1517 - 1525
Main Authors:	Cheng, Jie-Fei, Chen, Mi, Wallace, David, Tith, Souvothy, Haramura, Masayuki, Liu, Bin, Mak, Chi Ching, Arrhenius, Thomas, Reily, Sean, Brown, Steven, Thorn, Vicki, Harmon, Charles, Barr, Rick, Dyck, Jason R. B, Lopaschuk, Gary D, Nadzan, Alex M
Format:	Journal Article
Language:	English
Published:	Washington, DC American Chemical Society 09-03-2006
Subjects:	Animals Biological and medical sciences Carboxy-Lyases - antagonists & inhibitors Cardiovascular system Energy Metabolism - drug effects Fatty Acids - metabolism Glucose - metabolism In Vitro Techniques Male Malonyl Coenzyme A - metabolism Medical sciences Miscellaneous Morpholines - chemical synthesis Morpholines - chemistry Morpholines - pharmacology Myocardial Ischemia - drug therapy Myocardium - enzymology Myocardium - metabolism Oxidation-Reduction Pharmacology. Drug treatments Phenylurea Compounds - chemical synthesis Phenylurea Compounds - chemistry Phenylurea Compounds - pharmacology Rats Rats, Sprague-Dawley Structure-Activity Relationship Swine Heart Rat Cardiovascular disease Lyases Morpholine derivatives Ex vivo Ischemia Structure activity relation Carboxy-lyases Tertiary alcohol Ureas Small molecule Chemical synthesis Ungulata Enzyme Rodentia Enzyme inhibitor Malonyl-CoA decarboxylase In vitro Pig Carbon-carbon lyases Vertebrata Experimental disease Mammalia Treatment Animal Organic fluorine compounds Benzenic compound Artiodactyla
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Summary:	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.
Bibliography:	istex:EFC8050E0527A719E65A26AB5C1DFC2DB136DA56 ark:/67375/TPS-2ZKZF5SR-C ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm050109n