title: Identification of a new class of glucokinase activators through structure-based design.
abstract: Glucose flux through glucokinase (GK) controls insulin release from the pancreas in response to high glucose concentrations. Glucose flux through GK also contributes to reducing hepatic glucose output. Because many individuals with type 2 diabetes appear to have an inadequacy or defect in one or both of these processes, compounds that can activate GK may serve as effective treatments for type 2 diabetes. Herein we report the identification and initial optimization of a novel series of allosteric glucokinase activators (GKAs). We discovered an initial thiazolylamino pyridine-based hit that was optimized using a structure-based design strategy and identified 26 as an early lead. Compound 26 demonstrated a good balance of in vitro potency and enzyme kinetic parameters and demonstrated blood glucose reductions in oral glucose tolerance tests in both C57BL/6J mice and high-fat fed Zucker diabetic fatty rats.
authors.affiliation: Array BioPharma , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Hinklin
authors.forename: Steven A
authors.initials: SA
authors.lastname: Boyd
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Chicarelli
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Condroski
authors.forename: Walter E
authors.initials: WE
authors.lastname: DeWolf
authors.forename: Patrice A
authors.initials: PA
authors.lastname: Lee
authors.forename: Waiman
authors.initials: W
authors.lastname: Lee
authors.forename: Ajay
authors.initials: A
authors.lastname: Singh
authors.forename: Laurie
authors.initials: L
authors.lastname: Thomas
authors.forename: Walter C
authors.initials: WC
authors.lastname: Voegtli
authors.forename: Lance
authors.initials: L
authors.lastname: Williams
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Aicher
mesh_terms: D000494:Allosteric Regulation; D000631:Aminopyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D020536:Enzyme Activators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005941:Glucokinase / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D011924:Rats, Zucker; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D055815:Young Adult
chemical_list: C585156:5-(2-(1H-imidazol-1-yl)ethylthio)-3-(benzyloxy)-N-(4-isopropylthiazol-2-yl)pyridin-2-amine; D000631:Aminopyridines; D020536:Enzyme Activators; D007004:Hypoglycemic Agents; D013844:Thiazoles; D005941:Glucokinase