title: Maximizing lipophilic efficiency: the use of Free-Wilson analysis in the design of inhibitors of acetyl-CoA carboxylase.
abstract: This paper describes the design and synthesis of a novel series of dual inhibitors of acetyl-CoA carboxylase 1 and 2 (ACC1 and ACC2). Key findings include the discovery of an initial lead that was modestly potent and subsequent medicinal chemistry optimization with a focus on lipophilic efficiency (LipE) to balance overall druglike properties. Free-Wilson methodology provided a clear breakdown of the contributions of specific structural elements to the overall LipE, a rationale for prioritization of virtual compounds for synthesis, and a highly successful prediction of the LipE of the resulting analogues. Further preclinical assays, including in vivo malonyl-CoA reduction in both rat liver (ACC1) and rat muscle (ACC2), identified an advanced analogue that progressed to regulatory toxicity studies.
authors.affiliation: Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States. kevin.freeman-cook@pfizer.com
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Freeman-Cook
authors.forename: Paul
authors.initials: P
authors.lastname: Amor
authors.forename: Scott
authors.initials: S
authors.lastname: Bader
authors.forename: Leanne M
authors.initials: LM
authors.lastname: Buzon
authors.forename: Steven B
authors.initials: SB
authors.lastname: Coffey
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Corbett
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Dirico
authors.forename: Shawn D
authors.initials: SD
authors.lastname: Doran
authors.forename: Richard L
authors.initials: RL
authors.lastname: Elliott
authors.forename: William
authors.initials: W
authors.lastname: Esler
authors.forename: Angel
authors.initials: A
authors.lastname: Guzman-Perez
authors.forename: Kevin E
authors.initials: KE
authors.lastname: Henegar
authors.forename: Janet A
authors.initials: JA
authors.lastname: Houser
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Jones
authors.forename: Chris
authors.initials: C
authors.lastname: Limberakis
authors.forename: Katherine
authors.initials: K
authors.lastname: Loomis
authors.forename: Kirk
authors.initials: K
authors.lastname: McPherson
authors.forename: Sharad
authors.initials: S
authors.lastname: Murdande
authors.forename: Kendra L
authors.initials: KL
authors.lastname: Nelson
authors.forename: Dennis
authors.initials: D
authors.lastname: Phillion
authors.forename: Betsy S
authors.initials: BS
authors.lastname: Pierce
authors.forename: Wei
authors.initials: W
authors.lastname: Song
authors.forename: Eliot
authors.initials: E
authors.lastname: Sugarman
authors.forename: Susan
authors.initials: S
authors.lastname: Tapley
authors.forename: Meihua
authors.initials: M
authors.lastname: Tu
authors.forename: Zhengrong
authors.initials: Z
authors.lastname: Zhao
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors*; D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry; D015195:Drug Design; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry; D007191:Indazoles / Q000138:chemical synthesis* / Q000737:chemistry; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008099:Liver / Q000201:enzymology; D018482:Muscle, Skeletal / Q000201:enzymology; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: C571191:2'-(tert-butyl)-1-(1H-indazole-5-carbonyl)-2'H-spiro(piperidine-4,5'-pyrano(3,2-c)pyrazol)-7'(6'H)-one; D001562:Benzimidazoles; D007004:Hypoglycemic Agents; D007191:Indazoles; D007211:Indoles; D007527:Isoenzymes; D011720:Pyrazoles; D013141:Spiro Compounds; D000103:Acetyl-CoA Carboxylase