Anthranilimide based glycogen phosphorylase inhibitors for the treatment of type 2 diabetes. Part 3: X-ray crystallographic characterization, core and urea optimization and in vivo efficacy.
Key binding interactions of the anthranilimide based glycogen phosphorylase a (GPa) inhibitor 2 from X-ray crystallography studies are described. This series of compounds bind to the AMP site of GP. Using the binding information the core and the phenyl urea moieties were optimized. This work culminated in the identification of compounds with single nanomolar potency as well as in vivo efficacy in a diabetic model.
Thomson
Stephen A
SA
Metabolic Center for Excellence in Drug Discovery, GlaxoSmithKline, 5 Moore Drive, PO Box 13398, Research Triangle Park, NC 27705, USA. stephen.a.thomson@gsk.com
Banker
Pierette
P
Bickett
D Mark
DM
Boucheron
Joyce A
JA
Carter
H Luke
HL
Clancy
Daphne C
DC
Cooper
Joel P
JP
Dickerson
Scott H
SH
Garrido
Dulce M
DM
Nolte
Robert T
RT
Peat
Andrew J
AJ
Sheckler
Lauren R
LR
Sparks
Steven M
SM
Tavares
Francis X
FX
Wang
Liping
L
Wang
Tony Y
TY
Weiel
James E
JE
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004195:Disease Models, Animal; D024981:Glycogen Phosphorylase / Q000037:antagonists & inhibitors*; D007004:Hypoglycemic Agents / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008968:Molecular Conformation; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014508:Urea / Q000494:pharmacology; D062367:ortho-Aminobenzoates / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D062367:ortho-Aminobenzoates; D014508:Urea; D024981:Glycogen Phosphorylase; C000219:anthranilamide