Discovery of triazolone derivatives as novel, potent stearoyl-CoA desaturase-1 (SCD1) inhibitors

被引：10

作者：

Sun, Shaoyi ^{[1
]}

Zhang, Zaihui ^{[1
]}

Pokrovskaia, Natalia ^{[1
]}

Chowdhury, Sultan ^{[1
]}

Jia, Qi ^{[1
]}

Chang, Elaine ^{[1
]}

Khakh, Kuldip ^{[1
]}

Kwan, Rainbow ^{[1
]}

McLaren, David G. ^{[1
]}

Radomski, Chris C. ^{[1
]}

Ratkay, Leslie G. ^{[1
]}

Fu, Jianmin ^{[1
]}

Dales, Natalie A. ^{[2
]}

Winther, Michael D. ^{[1
]}

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 | 2015年 / 23卷 / 03期

关键词：

Stearoyl-CoA desaturase; Thiazolytriazolone; Pyrazolyltriazolone; Desaturation index; HETEROARYL-PIPERIDINE DERIVATIVES; INDUCED GENE-EXPRESSION; 3T3-L1; PREADIPOCYTES; INSULIN-RESISTANCE; METABOLIC SYNDROME; SKELETAL-MUSCLE; OBESITY; MICE; IDENTIFICATION; ASSOCIATIONS;

D O I：

10.1016/j.bmc.2014.12.014

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Stearoyl-CoA desaturase-1 (SCD1) plays an important role in lipid metabolism. Inhibition of SCD1 activity represents a potential novel approach for the treatment of metabolic diseases such as obesity, type 2 diabetes and dyslipidemia, as well as skin diseases, acne and cancer. Herein, we report the synthesis and structure-activity relationships (SAR) of a series of novel triazolone derivatives, culminating in the identification of pyrazolyltriazolone 17a, a potent SCD1 inhibitor, which reduced plasma C16:1/C16:0 triglycerides desaturation index (DI) in an acute Lewis rat model in a dose dependent manner, with an ED50 of 4.6 mg/kg. In preliminary safety studies, compound 17a did not demonstrate adverse effects related to SCD1 inhibition after repeat dosing at 100 mg/kg. Together, these data suggest that sufficient safety margins can be achieved with certain SCD1 inhibitors, thus allowing exploration of clinical utility in metabolic disease settings. (C) 2014 Elsevier Ltd. All rights reserved.

引用

收藏

页码：455 / 465

页数：11

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