title: Discovery of small molecule isozyme non-specific inhibitors of mammalian acetyl-CoA carboxylase 1 and 2.
abstract: Screening Pfizer's compound library resulted in the identification of weak acetyl-CoA carboxylase inhibitors, from which were obtained rACC1 CT-domain co-crystal structures. Utilizing HTS hits and structure-based drug discovery, a more rigid inhibitor was designed and led to the discovery of sub-micromolar, spirochromanone non-specific ACC inhibitors. Low nanomolar, non-specific ACC-isozyme inhibitors that exhibited good rat pharmacokinetics were obtained from this chemotype.
authors.affiliation: Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA. jmc1983mac@gmail.com
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Corbett
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Freeman-Cook
authors.forename: Richard
authors.initials: R
authors.lastname: Elliott
authors.forename: Felix
authors.initials: F
authors.lastname: Vajdos
authors.forename: Francis
authors.initials: F
authors.lastname: Rajamohan
authors.forename: Darcy
authors.initials: D
authors.lastname: Kohls
authors.forename: Eric
authors.initials: E
authors.lastname: Marr
authors.forename: Hailong
authors.initials: H
authors.lastname: Zhang
authors.forename: Liang
authors.initials: L
authors.lastname: Tong
authors.forename: Meihua
authors.initials: M
authors.lastname: Tu
authors.forename: Sharad
authors.initials: S
authors.lastname: Murdande
authors.forename: Shawn D
authors.initials: SD
authors.lastname: Doran
authors.forename: Janet A
authors.initials: JA
authors.lastname: Houser
authors.forename: Wei
authors.initials: W
authors.lastname: Song
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Jones
authors.forename: Steven B
authors.initials: SB
authors.lastname: Coffey
authors.forename: Leanne
authors.initials: L
authors.lastname: Buzon
authors.forename: Martha L
authors.initials: ML
authors.lastname: Minich
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Dirico
authors.forename: Susan
authors.initials: S
authors.lastname: Tapley
authors.forename: R Kirk
authors.initials: RK
authors.lastname: McPherson
authors.forename: Eliot
authors.initials: E
authors.lastname: Sugarman
authors.forename: H James
authors.initials: HJ
authors.lastname: Harwood
authors.forename: William
authors.initials: W
authors.lastname: Esler
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000818:Animals; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008958:Models, Molecular; D051381:Rats; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007527:Isoenzymes; D054852:Small Molecule Libraries; D000103:Acetyl-CoA Carboxylase