Identification, optimisation and in vivo evaluation of oxadiazole DGAT-1 inhibitors for the treatment of obesity and diabetes
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- 作者：William McCoull ; william.mccoull@astrazeneca.com ; 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 ; Thorsten Nowak ; Martin J. Packer ; Alleyn T. Plowright ; John Revill ; Paul Schofield ; Chris Sheldon ; Steve Stokes ; Andrew V. Turnbull ; Steven J.Y. Wang ; David P. Whalley ; J. Matthew Wood
- 关键词：DGAT ; Oxadiazole ; LLE ; Obesity ; PK/PD
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2012
- 出版时间：15 June, 2012
- 年：2012
- 卷：22
- 期：12
- 页码：3873-3878
- 全文大小：1111 K
文摘
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.