title: N-{3-[2-(4-alkoxyphenoxy)thiazol-5-yl]-1-methylprop-2-ynyl}carboxy derivatives as acetyl-coA carboxylase inhibitors--improvement of cardiovascular and neurological liabilities via structural modifications.
abstract: A preliminary safety evaluation of ACC2 inhibitor 1-(S) revealed serious neurological and cardiovascular liabilities of this chemotype. A systematic structure-toxicity relationship study identified the alkyne linker as the key motif responsible for these adverse effects. Toxicogenomic studies in rats showed that 1-(R) and 1-(S) induced gene expression patterns similar to that seen with several known cardiotoxic agents such as doxorubicin. Replacement of the alkyne with alternative linker groups led to a new series of ACC inhibitors with drastically improved cardiovascular and neurological profiles.
authors.affiliation: 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: Nathan L
authors.initials: NL
authors.lastname: Lubbers
authors.forename: Yi
authors.initials: Y
authors.lastname: Yang
authors.forename: David W A
authors.initials: DW
authors.lastname: Beno
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Widomski
authors.forename: Tianyuan
authors.initials: T
authors.lastname: Zhang
authors.forename: T Matthew
authors.initials: TM
authors.lastname: Hansen
authors.forename: Robert F
authors.initials: RF
authors.lastname: Keyes
authors.forename: Jeffrey F
authors.initials: JF
authors.lastname: Waring
authors.forename: Sherry L
authors.initials: SL
authors.lastname: Carroll
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Wang
authors.forename: Rongqi
authors.initials: R
authors.lastname: Wang
authors.forename: Christine H
authors.initials: CH
authors.lastname: Healan-Greenberg
authors.forename: Eric A
authors.initials: EA
authors.lastname: Blomme
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Beutel
authors.forename: Hing L
authors.initials: HL
authors.lastname: Sham
authors.forename: Heidi S
authors.initials: HS
authors.lastname: Camp
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors*; D000284:Administration, Oral; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D015870:Gene Expression / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects*; D007262:Infusions, Intravenous; D008297:Male; D009206:Myocardium / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000009:adverse effects / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D013844:Thiazoles; D000103:Acetyl-CoA Carboxylase