title: 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.
abstract: 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.
authors.affiliation: 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
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Thomson
authors.forename: Pierette
authors.initials: P
authors.lastname: Banker
authors.forename: D Mark
authors.initials: DM
authors.lastname: Bickett
authors.forename: Joyce A
authors.initials: JA
authors.lastname: Boucheron
authors.forename: H Luke
authors.initials: HL
authors.lastname: Carter
authors.forename: Daphne C
authors.initials: DC
authors.lastname: Clancy
authors.forename: Joel P
authors.initials: JP
authors.lastname: Cooper
authors.forename: Scott H
authors.initials: SH
authors.lastname: Dickerson
authors.forename: Dulce M
authors.initials: DM
authors.lastname: Garrido
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: Steven M
authors.initials: SM
authors.lastname: Sparks
authors.forename: Francis X
authors.initials: FX
authors.lastname: Tavares
authors.forename: Liping
authors.initials: L
authors.lastname: Wang
authors.forename: Tony Y
authors.initials: TY
authors.lastname: Wang
authors.forename: James E
authors.initials: JE
authors.lastname: Weiel
mesh_terms: 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*
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D062367:ortho-Aminobenzoates; D014508:Urea; D024981:Glycogen Phosphorylase; C000219:anthranilamide