Design of a potent, soluble glucokinase activator with excellent in vivo efficacy.
The optimisation of a series of glucokinase activators is described, including attempts to uncouple the relationship between potency and plasma protein binding, and to better understand the key pharmacokinetic properties of the series. The use of unbound clearance as an optimisation parameter facilitated the identification of GKA50, a compound which combines excellent potency and pharmacokinetics with good free drug levels and solubility, and exhibits in vivo efficacy at 1mg/kg po in an acute rat OGTT model.
McKerrecher
Darren
D
Cardiovascular and Gastrointestinal Research Area, AstraZeneca R&D, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK. darren.mckerrecher@astrazeneca.com
Allen
Joanne V
JV
Caulkett
Peter W R
PW
Donald
Craig S
CS
Fenwick
Mark L
ML
Grange
Emma
E
Johnson
Keith M
KM
Johnstone
Craig
C
Jones
Clifford D
CD
Pike
Kurt G
KG
Rayner
John W
JW
Walker
Rolf P
RP
D015195:Drug Design; D020536:Enzyme Activators / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D005941:Glucokinase / Q000378:metabolism*
D020536:Enzyme Activators; D005941:Glucokinase