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.
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.
Uto
Yoshikazu
Y
Medicinal Chemistry Research Laboratories I, Daiichi Sankyo Co., Ltd, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. uto.yoshikazu.pw@daiichisankyo.co.jp
Ogata
Tsuneaki
T
Kiyotsuka
Yohei
Y
Miyazawa
Yuriko
Y
Ueno
Yuko
Y
Kurata
Hitoshi
H
Deguchi
Tsuneo
T
Yamada
Makiko
M
Watanabe
Nobuaki
N
Takagi
Toshiyuki
T
Wakimoto
Satoko
S
Okuyama
Ryo
R
Konishi
Masahiro
M
Kurikawa
Nobuya
N
Kono
Keita
K
Osumi
Jun
J
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
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