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

Yoshikazu Uto; Tsuneaki Ogata; Yohei Kiyotsuka; Yuriko Miyazawa; Yuko Ueno; Hitoshi Kurata; Tsuneo Deguchi; Makiko Yamada; Nobuaki Watanabe; Toshiyuki Takagi; Satoko Wakimoto; Ryo Okuyama; Masahiro Konishi; Nobuya Kurikawa; Keita Kono; Jun Osumi

doi:10.1016/j.bmcl.2009.05.123

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

Bioorg Med Chem Lett. 2009 Aug 1;19(15):4159-66. doi: 10.1016/j.bmcl.2009.05.123. Epub 2009 Jun 6.

Authors

Yoshikazu Uto¹, Tsuneaki Ogata, Yohei Kiyotsuka, Yuriko Miyazawa, Yuko Ueno, Hitoshi Kurata, Tsuneo Deguchi, Makiko Yamada, Nobuaki Watanabe, Toshiyuki Takagi, Satoko Wakimoto, Ryo Okuyama, Masahiro Konishi, Nobuya Kurikawa, Keita Kono, Jun Osumi

Affiliation

¹ Medicinal Chemistry Research Laboratories I, Daiichi Sankyo Co., Ltd, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. uto.yoshikazu.pw@daiichisankyo.co.jp

PMID: 19541482
DOI: 10.1016/j.bmcl.2009.05.123

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.

MeSH terms

Administration, Oral
Animals
Area Under Curve
Benzamides / chemical synthesis*
Benzamides / pharmacology
Chemistry, Pharmaceutical / methods*
Dose-Response Relationship, Drug
Drug Design
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / pharmacology
Humans
Inhibitory Concentration 50
Mice
Mice, Inbred C57BL
Models, Chemical
Stearoyl-CoA Desaturase / antagonists & inhibitors*
Stearoyl-CoA Desaturase / chemistry
Structure-Activity Relationship
Thiazoles / chemical synthesis*
Thiazoles / chemistry
Thiazoles / pharmacology

Substances

3-(2-hydroxyethoxy)-4-methoxy-N-(5-(3-trifluoromethylbenzyl)thiazol-2-yl)benzamide
Benzamides
Enzyme Inhibitors
Thiazoles
Stearoyl-CoA Desaturase