title: Design of a potent, soluble glucokinase activator with excellent in vivo efficacy.
abstract: 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.
authors.affiliation: Cardiovascular and Gastrointestinal Research Area, AstraZeneca R&D, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK. darren.mckerrecher@astrazeneca.com
authors.forename: Darren
authors.initials: D
authors.lastname: McKerrecher
authors.forename: Joanne V
authors.initials: JV
authors.lastname: Allen
authors.forename: Peter W R
authors.initials: PW
authors.lastname: Caulkett
authors.forename: Craig S
authors.initials: CS
authors.lastname: Donald
authors.forename: Mark L
authors.initials: ML
authors.lastname: Fenwick
authors.forename: Emma
authors.initials: E
authors.lastname: Grange
authors.forename: Keith M
authors.initials: KM
authors.lastname: Johnson
authors.forename: Craig
authors.initials: C
authors.lastname: Johnstone
authors.forename: Clifford D
authors.initials: CD
authors.lastname: Jones
authors.forename: Kurt G
authors.initials: KG
authors.lastname: Pike
authors.forename: John W
authors.initials: JW
authors.lastname: Rayner
authors.forename: Rolf P
authors.initials: RP
authors.lastname: Walker
mesh_terms: D015195:Drug Design; D020536:Enzyme Activators / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D005941:Glucokinase / Q000378:metabolism*
chemical_list: D020536:Enzyme Activators; D005941:Glucokinase