Anthranilimide-based glycogen phosphorylase inhibitors for the treatment of type 2 diabetes: 1. Identification of 1-amino-1-cycloalkyl carboxylic acid headgroups.
Optimization of the amino acid residue within a series of anthranilimide-based glycogen phosphorylase inhibitors is described. These studies culminated in the identification of anthranilimides 16 and 22 which displayed potent in vitro inhibition of GPa in addition to reduced inhibition of CYP2C9 and excellent pharmacokinetic properties.
Sparks
Steven M
SM
Metabolic Center for Excellence in Drug Discovery, GlaxoSmithKline, PO Box 13398, Research Triangle Park, NC 27705, USA. steven.m.sparks@gsk.com
Banker
Pierette
P
Bickett
David M
DM
Carter
H Luke
HL
Clancy
Daphne C
DC
Dickerson
Scott H
SH
Dwornik
Kate A
KA
Garrido
Dulce M
DM
Golden
Pamela L
PL
Nolte
Robert T
RT
Peat
Andrew J
AJ
Sheckler
Lauren R
LR
Tavares
Francis X
FX
Thomson
Stephen A
SA
Wang
Liping
L
Weiel
James E
JE
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D002264:Carboxylic Acids / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D018360:Crystallography, X-Ray; D065729:Cytochrome P-450 CYP2C9; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004285:Dogs; D015195:Drug Design; D005998:Glycine / Q000737:chemistry; D024981:Glycogen Phosphorylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007094:Imides / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008099:Liver / Q000201:enzymology; D008968:Molecular Conformation; D051381:Rats; D062367:ortho-Aminobenzoates / Q000737:chemistry / Q000494:pharmacology*
D002264:Carboxylic Acids; D007094:Imides; D062367:ortho-Aminobenzoates; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D024981:Glycogen Phosphorylase; D005998:Glycine