title: Discovery of novel (4-piperidinyl)-piperazines as potent and orally active acetyl-CoA carboxylase 1/2 non-selective inhibitors: F-Boc and triF-Boc groups are acid-stable bioisosteres for the Boc group.
abstract: Novel (4-piperidinyl)-piperazine derivatives were synthesized and evaluated as ACC1/2 non-selective inhibitors. Optimization of the substituents on the nitrogen of the piperidine ring led to the identification of the fluorine substituted tert-butoxycarbonyl group. Advanced analog, 1,1,1-trifluoro-2-methylpropan-2-yl 4-{4-[(2-amino-6-methyl-1-benzothiophen-3-yl)carbonyl]piperazin-1-yl}piperidine-1-carboxylate (12c) showed potent inhibitory activities in enzyme-assay and cell-based assays. Compound 12c also exhibited reduction of hepatic de novo fatty acid synthesis in rats after oral administration.
authors.affiliation: Medicinal Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd, Kita-ku, Saitama-shi, Saitama, Japan. tomomichi.chonan@po.rd.taisho.co.jp
authors.forename: Tomomichi
authors.initials: T
authors.lastname: Chonan
authors.forename: Daisuke
authors.initials: D
authors.lastname: Wakasugi
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yamamoto
authors.forename: Miyoko
authors.initials: M
authors.lastname: Yashiro
authors.forename: Takahiro
authors.initials: T
authors.lastname: Oi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Tanaka
authors.forename: Ayumi
authors.initials: A
authors.lastname: Ohoka-Sugita
authors.forename: Fusayo
authors.initials: F
authors.lastname: Io
authors.forename: Hiroko
authors.initials: H
authors.lastname: Koretsune
authors.forename: Akira
authors.initials: A
authors.lastname: Hiratate
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors* / Q000145:classification; D000284:Administration, Oral; D000818:Animals; D005461:Fluorine / Q000737:chemistry*; D005563:Formic Acid Esters / Q000737:chemistry*; D015394:Molecular Structure; D000077489:Piperazine; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D005563:Formic Acid Esters; D010879:Piperazines; D010880:Piperidines; C000345:t-butyloxycarbonyl group; D000077489:Piperazine; D005461:Fluorine; C032727:piperidine; D000103:Acetyl-CoA Carboxylase