Anthranilimide-based glycogen phosphorylase inhibitors for the treatment of Type 2 diabetes: 2. Optimization of serine and threonine ether amino acid residues.
Optimization of the amino acid residue of a series of anthranilimide-based glycogen phosphorylase inhibitors is described leading to the identification of serine and threonine ether analogs. t-Butylthreonine analog 20 displayed potent in vitro inhibition of GPa, low potential for P450 inhibition, and excellent pharmacokinetic properties.
Sparks
Steven M
SM
Metabolic Center for Excellence in Drug Discovery, GlaxoSmithKline, 5 Moore Drive, PO Box 13398, Research Triangle Park, NC 27705, USA. Steven.M.Sparks@gsk.com
Banker
Pierette
P
Bickett
David M
DM
Clancy
Daphne C
DC
Dickerson
Scott H
SH
Garrido
Dulce M
DM
Golden
Pamela L
PL
Peat
Andrew J
AJ
Sheckler
Lauren R
LR
Tavares
Francis X
FX
Thomson
Stephen A
SA
Weiel
James E
JE
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D018360:Crystallography, X-Ray; D065729:Cytochrome P-450 CYP2C9; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D015195:Drug Design; D005998:Glycine / Q000737:chemistry; D024981:Glycogen Phosphorylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007094:Imides / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D008099:Liver / Q000201:enzymology; D008956:Models, Chemical; D051381:Rats; D012694:Serine / Q000737:chemistry*; D013912:Threonine / Q000737:chemistry*; D062367:ortho-Aminobenzoates / Q000737:chemistry*
D007094:Imides; D062367:ortho-Aminobenzoates; D013912:Threonine; D012694:Serine; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D024981:Glycogen Phosphorylase; D005998:Glycine