title: Identification of 2-[2-(4-tert-butylphenyl)ethyl]-N-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide (29) as an orally available MGAT2 inhibitor.
abstract: MGAT2 (monoacylglycerol acyltransferase 2) is expected to be an attractive target for the drug treatment of obesity, diabetes, and other disease. We describe our exploration and structure-activity relationship (SAR) study of 2,3-dihydro-1H-isoindole-5-sulfonamide derivatives. In this study, we identified 29 as an orally available inhibitor of MGAT2 through optimization especially in terms of solubility. This compound exhibited moderate potency in the enzyme inhibitory assay (IC50 = 1522 nM) and significant suppression of fat absorption (57% inhibition) in mice oral lipid tolerance test.
authors.affiliation: Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd, 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan. Electronic address: t-busujima@so.taisho.co.jp.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Busujima
authors.affiliation: Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd, 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd, 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan.
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Shirasaki
authors.affiliation: Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd, 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Munetomo
authors.affiliation: Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd, 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan.
authors.forename: Masako
authors.initials: M
authors.lastname: Saito
authors.affiliation: Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd, 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan.
authors.forename: Kiyokazu
authors.initials: K
authors.lastname: Kitano
authors.affiliation: Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co., Ltd, 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan.
authors.forename: Toshiya
authors.initials: T
authors.lastname: Minagawa
authors.affiliation: Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co., Ltd, 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Pharmaceutical Science Laboratories, Taisho Pharmaceutical Co., Ltd, 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Osaki
authors.affiliation: Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd, 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan.
authors.forename: Nagaaki
authors.initials: N
authors.lastname: Sato
mesh_terms: D000818:Animals; D003920:Diabetes Mellitus / Q000188:drug therapy*; D006801:Humans; D051379:Mice; D017351:N-Acetylglucosaminyltransferases / Q000037:antagonists & inhibitors*; D009765:Obesity / Q000188:drug therapy*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry*; D044005:Tetrahydroisoquinolines / Q000737:chemistry*
chemical_list: D013449:Sulfonamides; D044005:Tetrahydroisoquinolines; D017351:N-Acetylglucosaminyltransferases; C063313:alpha-1,6-mannosyl-glycoprotein beta-1,2-N-acetylglucosaminyltransferase
keywords: Fat absorption; MGAT2; Monoacylglycerol acyltransferase; Oral lipid tolerance test; Tetrahydroisoquinoline