title: Anthranilimide-based glycogen phosphorylase inhibitors for the treatment of type 2 diabetes: 1. Identification of 1-amino-1-cycloalkyl carboxylic acid headgroups.
abstract: 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.
authors.affiliation: Metabolic Center for Excellence in Drug Discovery, GlaxoSmithKline, PO Box 13398, Research Triangle Park, NC 27705, USA. steven.m.sparks@gsk.com
authors.forename: Steven M
authors.initials: SM
authors.lastname: Sparks
authors.forename: Pierette
authors.initials: P
authors.lastname: Banker
authors.forename: David M
authors.initials: DM
authors.lastname: Bickett
authors.forename: H Luke
authors.initials: HL
authors.lastname: Carter
authors.forename: Daphne C
authors.initials: DC
authors.lastname: Clancy
authors.forename: Scott H
authors.initials: SH
authors.lastname: Dickerson
authors.forename: Kate A
authors.initials: KA
authors.lastname: Dwornik
authors.forename: Dulce M
authors.initials: DM
authors.lastname: Garrido
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Golden
authors.forename: Robert T
authors.initials: RT
authors.lastname: Nolte
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Peat
authors.forename: Lauren R
authors.initials: LR
authors.lastname: Sheckler
authors.forename: Francis X
authors.initials: FX
authors.lastname: Tavares
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Thomson
authors.forename: Liping
authors.initials: L
authors.lastname: Wang
authors.forename: James E
authors.initials: JE
authors.lastname: Weiel
mesh_terms: 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*
chemical_list: 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