title: Anthranilimide-based glycogen phosphorylase inhibitors for the treatment of Type 2 diabetes: 2. Optimization of serine and threonine ether amino acid residues.
abstract: 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.
authors.affiliation: 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
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: Daphne C
authors.initials: DC
authors.lastname: Clancy
authors.forename: Scott H
authors.initials: SH
authors.lastname: Dickerson
authors.forename: Dulce M
authors.initials: DM
authors.lastname: Garrido
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Golden
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: James E
authors.initials: JE
authors.lastname: Weiel
mesh_terms: 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*
chemical_list: 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