title: Phenoxy thiazole derivatives as potent and selective acetyl-CoA carboxylase 2 inhibitors: Modulation of isozyme selectivity by incorporation of phenyl ring substituents.
abstract: 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.
authors.affiliation: Metabolic Disease Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA. rick.clark@abbott.com
authors.forename: Richard F
authors.initials: RF
authors.lastname: Clark
authors.forename: Tianyuan
authors.initials: T
authors.lastname: Zhang
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Wang
authors.forename: Rongqi
authors.initials: R
authors.lastname: Wang
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Zhang
authors.forename: Heidi S
authors.initials: HS
authors.lastname: Camp
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Beutel
authors.forename: Hing L
authors.initials: HL
authors.lastname: Sham
authors.forename: Yu Gui
authors.initials: YG
authors.lastname: Gu
mesh_terms: 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
chemical_list: D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D007527:Isoenzymes; C520105:ACACB protein, human; D000103:Acetyl-CoA Carboxylase