Phenoxy thiazole derivatives as potent and selective acetyl-CoA carboxylase 2 inhibitors: Modulation of isozyme selectivity by incorporation of phenyl ring substituents.
A phenyl ring substitution strategy was employed to optimize the ACC2 potency and selectivity profiles of a recently discovered phenoxy thiazolyl series of acetyl-CoA carboxylase inhibitors. Ring substituents were shown to dramatically affect isozyme selectivity. Modifications that generally impart high levels of ACC2 selectivity (>3000-fold) while maintaining excellent ACC2 potency (IC50s approximately 9-20 nM) were identified.
Clark
Richard F
RF
Metabolic Disease Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA. rick.clark@abbott.com
Zhang
Tianyuan
T
Wang
Xiaojun
X
Wang
Rongqi
R
Zhang
Xiaolin
X
Camp
Heidi S
HS
Beutel
Bruce A
BA
Sham
Hing L
HL
Gu
Yu Gui
YG
D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry; D020128:Inhibitory Concentration 50; D007527:Isoenzymes / Q000737:chemistry; D008956:Models, Chemical; D008968:Molecular Conformation; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D007527:Isoenzymes; C520105:ACACB protein, human; D000103:Acetyl-CoA Carboxylase