title: Synthesis and structure-activity relationship of small-molecule malonyl coenzyme A decarboxylase inhibitors.
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.
authors.affiliation: Department of Chemistry, Chugai Pharma USA, LLC., 6225 Nancy Ridge Drive, San Diego, California 92121, USA. jcheng@trlusa.com
authors.forename: Jie-Fei
authors.initials: JF
authors.lastname: Cheng
authors.forename: Mi
authors.initials: M
authors.lastname: Chen
authors.forename: David
authors.initials: D
authors.lastname: Wallace
authors.forename: Souvothy
authors.initials: S
authors.lastname: Tith
authors.forename: Masayuki
authors.initials: M
authors.lastname: Haramura
authors.forename: Bin
authors.initials: B
authors.lastname: Liu
authors.forename: Chi Ching
authors.initials: CC
authors.lastname: Mak
authors.forename: Thomas
authors.initials: T
authors.lastname: Arrhenius
authors.forename: Sean
authors.initials: S
authors.lastname: Reily
authors.forename: Steven
authors.initials: S
authors.lastname: Brown
authors.forename: Vicki
authors.initials: V
authors.lastname: Thorn
authors.forename: Charles
authors.initials: C
authors.lastname: Harmon
authors.forename: Rick
authors.initials: R
authors.lastname: Barr
authors.forename: Jason R B
authors.initials: JR
authors.lastname: Dyck
authors.forename: Gary D
authors.initials: GD
authors.lastname: Lopaschuk
authors.forename: Alex M
authors.initials: AM
authors.lastname: Nadzan
mesh_terms: D000818:Animals; D002262:Carboxy-Lyases / Q000037:antagonists & inhibitors*; D004734:Energy Metabolism / Q000187:drug effects; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D008316:Malonyl Coenzyme A / Q000378:metabolism; D009025:Morpholines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017202:Myocardial Ischemia / Q000188:drug therapy; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism; D010084:Oxidation-Reduction; D010671:Phenylurea Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013552:Swine
chemical_list: D005227:Fatty Acids; D009025:Morpholines; D010671:Phenylurea Compounds; C509702:methyl 5-(N-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)morpholine-4-carboxamido)pentanoate; D008316:Malonyl Coenzyme A; D002262:Carboxy-Lyases; C021532:malonyl-CoA decarboxylase; D005947:Glucose