title: Identification of 2-[2-(4-tert-Butylphenyl)ethyl]-N-[4-(3-cyclopentylpropyl)-2-fluorophenyl]-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide as an Orally Active MGAT2 Inhibitor.
abstract: We previously reported 2-[2-(4-tert-butylphenyl)ethyl]-N-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide 2 as on orally available monoacylglycerol acyltransferase 2 (MGAT2) inhibitor which exhibited an in vivo efficacy at an oral dose of 100 mg/kg in a mouse oral lipid tolerance test. Further optimization of compound 2 to improve the intrinsic potency culminated in the identification of compound 11. Compound 11 showed a >50-fold lower IC50 against human MGAT2 enzyme than 2. Oral administration of 11 at a dose of 3 mg/kg in the oral lipid tolerance test resulted in significant suppression of triglyceride synthesis.
authors.affiliation: Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Busujima
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Tanaka
authors.forename: Kanako
authors.initials: K
authors.lastname: Iwakiri
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Shirasaki
authors.forename: Eiji
authors.initials: E
authors.lastname: Munetomo
authors.forename: Masako
authors.initials: M
authors.lastname: Saito
authors.forename: Aiko
authors.initials: A
authors.lastname: Masuko
authors.forename: Kiyokazu
authors.initials: K
authors.lastname: Kitano
authors.forename: Fusayo
authors.initials: F
authors.lastname: Io
authors.forename: Koji
authors.initials: K
authors.lastname: Kato
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Kamigaso
authors.forename: Akiko
authors.initials: A
authors.lastname: Nozoe
authors.forename: Nagaaki
authors.initials: N
authors.lastname: Sato
mesh_terms: D000284:Administration, Oral; D006801:Humans; D017351:N-Acetylglucosaminyltransferases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D044005:Tetrahydroisoquinolines; D017351:N-Acetylglucosaminyltransferases; C063313:alpha-1,6-mannosyl-glycoprotein beta-1,2-N-acetylglucosaminyltransferase