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

• Published in: Chemical & pharmaceutical bulletin Vol. 64; no. 3; pp. 228 - 238
• Main Authors: Busujima, Tsuyoshi, Tanaka, Hiroaki, Iwakiri, Kanako, Shirasaki, Yoshihisa, Munetomo, Eiji, Saito, Masako, Masuko, Aiko, Kitano, Kiyokazu, Io, Fusayo, Kato, Koji, Kamigaso, Shunsuke, Nozoe, Akiko, Sato, Nagaaki
• Format: Journal Article
• Language: English
• Published: Japan The Pharmaceutical Society of Japan 01-03-2016; Pharmaceutical Society of Japan; Japan Science and Technology Agency
• Subjects: Administration, Oral; fat absorption; Humans; monoacylglycerol acyltransferase 2; N-Acetylglucosaminyltransferases - antagonists & inhibitors; oral lipid tolerance test; Structure-Activity Relationship; tetrahydroisoquinoline; Tetrahydroisoquinolines - administration & dosage; Tetrahydroisoquinolines - chemistry; Tetrahydroisoquinolines - pharmacology
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.c15-00803

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.