Systematic evaluation of amide bioisosteres leading to the discovery of novel and potent thiazolylimidazolidinone inhibitors of SCD1 for the treatment of metabolic diseases

被引：18

作者：

Sun, Shaoyi ^{[1
]}

Zhang, Zaihui ^{[1
]}

Kodumuru, Vishnumurthy ^{[1
]}

Pokrovskaia, Natalia ^{[1
]}

Fonarev, Julia ^{[1
]}

Jia, Qi ^{[1
]}

Leung, Po-Yee ^{[2
]}

Tran, Jennifer ^{[2
]}

Ratkay, Leslie G. ^{[1
]}

McLaren, David G. ^{[1
]}

Radomski, Chris ^{[1
]}

Chowdhury, Sultan ^{[1
]}

Fu, Jianmin ^{[1
]}

Hubbard, Brian ^{[2
]}

Winther, Michael D. ^{[1
]}

Dales, Natalie A. ^{[2
]}

机构：

[1] Xenon Pharmaceut Inc, Burnaby, BC V5G 4W8, Canada

[2] Novartis Inst Biomed Res, Cambridge, MA 02139 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2014年 / 24卷 / 02期

关键词：

Stearoyl-CoA desaturase-1; SCD1; inhibitors; Amide bioisosteres; Thiazolylimidazolidinone; Desaturation index; STEAROYL-COA DESATURASE; INDUCED GENE-EXPRESSION; 3T3-L1; PREADIPOCYTES; MICE; ASSOCIATIONS; DELTA-5; OBESITY;

D O I：

10.1016/j.bmcl.2013.12.036

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Several five- and six-membered heterocycles were introduced to replace the C2-position amide bond of the original 2-aminothiazole-based hit compound 5. Specifically, replacement of the amide bond with an imidazolidinone moiety yielded a novel and potent thiazolylimidazolidinone series of SCD1 inhibitors. XEN723 (compound 22) was identified after optimization of the thiazolylimidazolidinone series. This compound demonstrated a 560-fold improvement in in vitro potency and reduced plasma desaturation indices in a dose dependent manner, with an EC50 of 4.5 mg/kg. (C) 2013 Elsevier Ltd. All rights reserved.

引用

页码：520 / 525

页数：6

共 34 条

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