title: Design of a potent, soluble glucokinase activator with increased pharmacokinetic half-life.
abstract: The continued optimization of a series of glucokinase activators is described, including attempts to understand the interplay between molecular structure and the composite parameter of unbound clearance. These studies resulted in the discovery of a new scaffold for glucokinase activators and further exploration of this scaffold led to the identification of GKA60. GKA60 maintains an excellent balance of potency and physical properties whilst possessing a significantly different, but complimentary, pre-clinical pharmacokinetic profile compared with the previously disclosed compound GKA50.
authors.affiliation: Cardiovascular and Gastrointestinal Research Area, AstraZeneca R&D, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK. kurt.pike@astrazeneca.com
authors.forename: Kurt G
authors.initials: KG
authors.lastname: Pike
authors.forename: Joanne V
authors.initials: JV
authors.lastname: Allen
authors.forename: Peter W R
authors.initials: PW
authors.lastname: Caulkett
authors.forename: David S
authors.initials: DS
authors.lastname: Clarke
authors.forename: Craig S
authors.initials: CS
authors.lastname: Donald
authors.forename: Mark L
authors.initials: ML
authors.lastname: Fenwick
authors.forename: Keith M
authors.initials: KM
authors.lastname: Johnson
authors.forename: Craig
authors.initials: C
authors.lastname: Johnstone
authors.forename: Darren
authors.initials: D
authors.lastname: McKerrecher
authors.forename: John W
authors.initials: JW
authors.lastname: Rayner
authors.forename: Rolf P
authors.initials: RP
authors.lastname: Walker
authors.forename: Ingrid
authors.initials: I
authors.lastname: Wilson
mesh_terms: D000818:Animals; D004285:Dogs; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects*; D020536:Enzyme Activators / Q000138:chemical synthesis* / Q000494:pharmacology*; D005941:Glucokinase / Q000378:metabolism*; D006207:Half-Life; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry* / Q000494:pharmacology; D015394:Molecular Structure; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D020536:Enzyme Activators; D007004:Hypoglycemic Agents; D011725:Pyridines; C520311:glucokinase activator compound 50; D005941:Glucokinase