Development of potent, orally active 1-substituted-3,4-dihydro-2-quinolone glycogen phosphorylase inhibitors.
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.
Birch
Alan M
AM
AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK. alan.birch@astrazeneca.com
Kenny
Peter W
PW
Oikonomakos
Nikos G
NG
Otterbein
Ludovic
L
Schofield
Paul
P
Whittamore
Paul R O
PR
Whalley
Dave P
DP
D000818:Animals; D001682:Biological Availability; D001798:Blood Proteins / Q000378:metabolism; D018938:Caco-2 Cells; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D024981:Glycogen Phosphorylase / Q000037:antagonists & inhibitors*; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007202:Indicators and Reagents; D008099:Liver / Q000201:enzymology; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D018482:Muscle, Skeletal / Q000201:enzymology; D011804:Quinolines / Q000138:chemical synthesis* / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats
D001798:Blood Proteins; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D007202:Indicators and Reagents; D011804:Quinolines; D024981:Glycogen Phosphorylase