Development of potent, orally active 1-substituted-3,4-dihydro-2-quinolone glycogen phosphorylase inhibitors

  • Bioorg Med Chem Lett. 2007 Jan 15;17(2):394-9. doi: 10.1016/j.bmcl.2006.10.037.
Alan M Birch  1 ,  Peter W Kenny ,  Nikos G Oikonomakos ,  Ludovic Otterbein ,  Paul Schofield ,  Paul R O Whittamore ,  Dave P Whalley
Affiliations
  • 1. AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK. [email protected]
PMID: 17095214 DOI: 10.1016/j.bmcl.2006.10.037
Abstract

A series of substituted 3,4-dihydro-2-quinolone glycogen Phosphorylase inhibitors, which have potential as antidiabetic agents, is described. Initial members of the series showed good enzyme inhibitory potency but poor physical properties. Optimisation of the 1-substituent led to 2,3-dihydroxypropyl compounds which showed good in vitro potency and improved physical properties, together with good DMPK profiles and acute in vivo efficacy in a rat model. X-ray crystallographic data are presented, showing an unexpected variety of binding orientations at the dimer interface site.