Synthesis and structure-activity relationships of N-{3-[2-(4-alkoxyphenoxy)thiazol-5-yl]-1- methylprop-2-ynyl}carboxy derivatives as selective acetyl-CoA carboxylase 2 inhibitors.
A structurally novel acetyl-CoA carboxylase (ACC) inhibitor is identified from high-throughput screening. A preliminary structure-activity relationship study led to the discovery of potent dual ACC1/ACC2 and ACC2 selective inhibitors against human recombinant ACC1 and ACC2. Selective ACC2 inhibitors exhibited IC50<20 nM and >1000-fold selectivity against ACC1. (S)-Enantiomer 9p exhibited high ACC2 activity and lowered muscle malonyl-CoA dose-dependently in acute rodent studies, whereas (R)-enantiomer 9o was weak and had no effect on the malonyl-CoA level.
Gu
Yu Gui
YG
Metabolic Disease Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 200 Abbott Park Road, Abbott Park, Illinois 60064, USA. yu-gui.y.gu@abbott.com
Weitzberg
Moshe
M
Clark
Richard F
RF
Xu
Xiangdong
X
Li
Qun
Q
Zhang
Tianyuan
T
Hansen
T Matthew
TM
Liu
Gang
G
Xin
Zhili
Z
Wang
Xiaojun
X
Wang
Rongqi
R
McNally
Teresa
T
Zinker
Bradley A
BA
Frevert
Ernst U
EU
Camp
Heidi S
HS
Camp
Heidi
H
Beutel
Bruce A
BA
Sham
Hing L
HL
D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors* / Q000235:genetics; D000480:Alkynes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics; D008316:Malonyl Coenzyme A / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
D000480:Alkynes; D007004:Hypoglycemic Agents; D007527:Isoenzymes; D011994:Recombinant Proteins; D013844:Thiazoles; D008316:Malonyl Coenzyme A; D000103:Acetyl-CoA Carboxylase