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

Authors: Birch, AM  Kenny, PW  Oikonomakos, NG  Otterbein, L  Schofield, P  Whittamore, PR  Whalley, DP 
Citation: Birch AM, etal., Bioorg Med Chem Lett. 2007 Jan 15;17(2):394-9. Epub 2006 Oct 19.
Pubmed: (View Article at PubMed) PMID:17095214
DOI: Full-text: DOI:10.1016/j.bmcl.2006.10.037

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.


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CRRD Object Information
CRRD ID: 1642820
Created: 2007-10-18
Species: All species
Last Modified: 2007-10-18
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.