Identification, optimisation and in vivo evaluation of oxadiazole DGAT-1 inhibitors for the treatment of obesity and diabetes

恶二唑 DGAT-1 抑制剂治疗肥胖症和糖尿病的鉴定、优化及体内评估

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作者：William McCoull, Matthew S Addie, Alan M Birch, Susan Birtles, Linda K Buckett, Roger J Butlin, Suzanne S Bowker, Scott Boyd, Stephen Chapman, Robert D M Davies, Craig S Donald, Clive P Green, Chloe Jenner, Paul D Kemmitt, Andrew G Leach, Graeme C Moody, Pablo Morentin Gutierrez, Nicholas J Newcombe

期刊：

Bioorganic & Medicinal Chemistry Letters

影响因子：

2.500

时间：

2012

起止号：

2012 Jun 15;22(12):3873-8.

doi：

10.1016/j.bmcl.2012.04.117

研究方向：

代谢

疾病类型：

糖尿病

Abstract

A novel series of DGAT-1 inhibitors was discovered from an oxadiazole amide high throughput screening (HTS) hit. Optimisation of potency and ligand lipophilicity efficiency (LLE) resulted in a carboxylic acid containing clinical candidate 53 (AZD3988), which demonstrated excellent DGAT-1 potency (0.6 nM), good pharmacokinetics and pre-clinical in vivo efficacy that could be rationalised through a PK/PD relationship.

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