title: 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.
abstract: 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.
authors.affiliation: 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
authors.forename: Yu Gui
authors.initials: YG
authors.lastname: Gu
authors.forename: Moshe
authors.initials: M
authors.lastname: Weitzberg
authors.forename: Richard F
authors.initials: RF
authors.lastname: Clark
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Xu
authors.forename: Qun
authors.initials: Q
authors.lastname: Li
authors.forename: Tianyuan
authors.initials: T
authors.lastname: Zhang
authors.forename: T Matthew
authors.initials: TM
authors.lastname: Hansen
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.forename: Zhili
authors.initials: Z
authors.lastname: Xin
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Wang
authors.forename: Rongqi
authors.initials: R
authors.lastname: Wang
authors.forename: Teresa
authors.initials: T
authors.lastname: McNally
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Zinker
authors.forename: Ernst U
authors.initials: EU
authors.lastname: Frevert
authors.forename: Heidi S
authors.initials: HS
authors.lastname: Camp
authors.forename: Heidi
authors.initials: H
authors.lastname: Camp
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Beutel
authors.forename: Hing L
authors.initials: HL
authors.lastname: Sham
mesh_terms: 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
chemical_list: D000480:Alkynes; D007004:Hypoglycemic Agents; D007527:Isoenzymes; D011994:Recombinant Proteins; D013844:Thiazoles; D008316:Malonyl Coenzyme A; D000103:Acetyl-CoA Carboxylase