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

  • Bioorg Med Chem Lett. 2012 Jun 15;22(12):3873-8. doi: 10.1016/j.bmcl.2012.04.117.
William McCoull  1 ,  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
Affiliations
  • 1. Cardiovascular & Gastrointestinal Innovative Medicines Unit, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK. [email protected]
PMID: 22608962 DOI: 10.1016/j.bmcl.2012.04.117
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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