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, 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.
Cheng
Jie-Fei
JF
Department of Chemistry, Chugai Pharma USA, LLC., 6225 Nancy Ridge Drive, San Diego, California 92121, USA. jcheng@trlusa.com
Chen
Mi
M
Wallace
David
D
Tith
Souvothy
S
Haramura
Masayuki
M
Liu
Bin
B
Mak
Chi Ching
CC
Arrhenius
Thomas
T
Reily
Sean
S
Brown
Steven
S
Thorn
Vicki
V
Harmon
Charles
C
Barr
Rick
R
Dyck
Jason R B
JR
Lopaschuk
Gary D
GD
Nadzan
Alex M
AM
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
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