title: Discovery of 2-pyridylureas as glucokinase activators.
abstract: Glucokinase (GK) is the rate-limiting step for insulin release from the pancreas in response to high levels of glucose. Flux through GK also contributes to reducing hepatic glucose output. Since many individuals with type 2 diabetes appear to have an inadequacy or defect in one or both of these processes, identifying compounds that can allosterically activate GK may address this issue. Herein we report the identification and initial optimization of a novel series of glucokinase activators (GKAs). Optimization led to the identification of 33 as a compound that displayed activity in an oral glucose tolerance test (OGTT) in normal and diabetic mice.
authors.affiliation: Array BioPharma Inc. , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Hinklin
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Aicher
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Anderson
authors.forename: Brian R
authors.initials: BR
authors.lastname: Baer
authors.forename: Steven A
authors.initials: SA
authors.lastname: Boyd
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Condroski
authors.forename: Walter E
authors.initials: WE
authors.lastname: DeWolf
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Kraser
authors.forename: Maralee
authors.initials: M
authors.lastname: McVean
authors.forename: Susan P
authors.initials: SP
authors.lastname: Rhodes
authors.forename: Hillary L
authors.initials: HL
authors.lastname: Sturgis
authors.forename: Walter C
authors.initials: WC
authors.lastname: Voegtli
authors.forename: Lance
authors.initials: L
authors.lastname: Williams
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Houze
mesh_terms: D000818:Animals; D055808:Drug Discovery; D020536:Enzyme Activators / Q000138:chemical synthesis* / Q000494:pharmacology; D005941:Glucokinase / Q000378:metabolism*; D005951:Glucose Tolerance Test; D008810:Mice, Inbred C57BL; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D014508:Urea / Q000031:analogs & derivatives*
chemical_list: D020536:Enzyme Activators; D011725:Pyridines; D014508:Urea; D005941:Glucokinase