title: Novel and potent inhibitors of stearoyl-CoA desaturase-1. Part II: Identification of 4-ethylamino-3-(2-hydroxyethoxy)-N-[5-(3-trifluoromethylbenzyl)thiazol-2-yl]benzamide and its biological evaluation.
abstract: The continuing investigation of SAR studies of 3-(2-hydroxyethoxy)-N-(5-benzylthiazol-2-yl)-benzamides as stearoyl-CoA desaturase-1 (SCD-1) inhibitors is reported. Our prior hit-to-lead effort resulted in the identification of 1a as a potent and orally efficacious SCD-1 inhibitor. Further optimization of the structural motif resulted in the identification of 4-ethylamino-3-(2-hydroxyethoxy)-N-[5-(3-trifluoromethylbenzyl)thiazol-2-yl]benzamide (37c) with sub nano molar IC(50) in both murine and human SCD-1 inhibitory assays. This compound demonstrated a dose-dependent decrease in the plasma desaturation index in C57BL/6J mice on a non-fat diet after 7 days of oral administration.
authors.affiliation: Medicinal Chemistry Research Laboratories I, Daiichi Sankyo Co., Ltd, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. uto.yoshikazu.pw@daiichisankyo.co.jp
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Uto
authors.forename: Tsuneaki
authors.initials: T
authors.lastname: Ogata
authors.forename: Yohei
authors.initials: Y
authors.lastname: Kiyotsuka
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Miyazawa
authors.forename: Yuko
authors.initials: Y
authors.lastname: Ueno
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kurata
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Deguchi
authors.forename: Makiko
authors.initials: M
authors.lastname: Yamada
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Watanabe
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Takagi
authors.forename: Satoko
authors.initials: S
authors.lastname: Wakimoto
authors.forename: Ryo
authors.initials: R
authors.lastname: Okuyama
authors.forename: Masahiro
authors.initials: M
authors.lastname: Konishi
authors.forename: Nobuya
authors.initials: N
authors.lastname: Kurikawa
authors.forename: Keita
authors.initials: K
authors.lastname: Kono
authors.forename: Jun
authors.initials: J
authors.lastname: Osumi
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001549:Benzamides / Q000138:chemical synthesis* / Q000494:pharmacology; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008810:Mice, Inbred C57BL; D008956:Models, Chemical; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C545364:3-(2-hydroxyethoxy)-4-methoxy-N-(5-(3-trifluoromethylbenzyl)thiazol-2-yl)benzamide; D001549:Benzamides; D004791:Enzyme Inhibitors; D013844:Thiazoles; D013230:Stearoyl-CoA Desaturase