Discovery, synthesis and biological evaluation of novel glucokinase activators.
The identification, synthesis and SAR of a novel series of glucokinase activators is described. The interplay between lipophilicity, potency and physical properties is discussed, and compound 22 highlighted as having a suitable balance. In vivo pharmacokinetic and acute efficacy studies on this compound are also presented.
McKerrecher
Darren
D
Cardiovascular and Gastrointestinal Research Area, AstraZeneca UK, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK. darren.mckerrecher@astrazeneca.com <darren.mckerrecher@astrazeneca.com>
Allen
Joanne V
JV
Bowker
Suzanne S
SS
Boyd
Scott
S
Caulkett
Peter W R
PW
Currie
Gordon S
GS
Davies
Christopher D
CD
Fenwick
Mark L
ML
Gaskin
Harold
H
Grange
Emma
E
Hargreaves
Rod B
RB
Hayter
Barry R
BR
James
Roger
R
Johnson
Keith M
KM
Johnstone
Craig
C
Jones
Clifford D
CD
Lackie
Sarah
S
Rayner
John W
JW
Walker
Rolf P
RP
D000818:Animals; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004789:Enzyme Activation / Q000502:physiology; D020536:Enzyme Activators / Q000138:chemical synthesis* / Q000494:pharmacology; D005260:Female; D005941:Glucokinase / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013844:Thiazoles / Q000138:chemical synthesis / Q000494:pharmacology
D020536:Enzyme Activators; C476008:RO-28-0450; D013844:Thiazoles; D005941:Glucokinase