Discovery of potent and orally available malonyl-CoA decarboxylase inhibitors as cardioprotective agents.
Discovery of 5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-4,5-dihydroisoxazole-3-carboxamides as a new class of malonyl-coenzyme A decarboxylase (MCD) inhibitors is described. tert-Butyl 3-(5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-4,5-dihydroisoxazole-3-carboxamido)butanoate (5, CBM-301940) exhibited excellent potency and in vivo PK/ADME properties. It is the most powerful stimulant of glucose oxidation reported to date in isolated working rat hearts. Compound 5 improved the cardiac efficiency and function in a rat heart global ischemia/reperfusion model, suggesting MCD inhibitors may be useful for the treatment of ischemic heart diseases.
Cheng
Jie-Fei
JF
Department of Chemistry, Chugai Pharma USA, LLC., 6275 Nancy Ridge Drive, San Diego, California 92121, USA. jcheng@trlusa.com
Huang
Yujin
Y
Penuliar
Richard
R
Nishimoto
Masahiro
M
Liu
Larry
L
Arrhenius
Thomas
T
Yang
Guang
G
O'leary
Eoin
E
Barbosa
Miguel
M
Barr
Rick
R
Dyck
Jason R B
JR
Lopaschuk
Gary D
GD
Nadzan
Alex M
AM
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002262:Carboxy-Lyases / Q000037:antagonists & inhibitors*; D002316:Cardiotonic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D018360:Crystallography, X-Ray; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008968:Molecular Conformation; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000503:physiopathology; D015425:Myocardial Reperfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D002316:Cardiotonic Agents; D007555:Isoxazoles; C513150:tert-butyl 3-(5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-4,5-dihydroisoxazole-3-carboxamido)butanoate; D002262:Carboxy-Lyases; C021532:malonyl-CoA decarboxylase