2. Academic Validation
  3. Identification, optimisation and in vivo evaluation of oxadiazole DGAT-1 inhibitors for the treatment of obesity and diabetes

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

Affiliation

  • 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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