Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Journal of medicinal chemistry, 2006-03, Vol.49 (5), p.1517-1525

Ort / Verlag

Washington, DC: American Chemical Society

Erscheinungsjahr

2006

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.