title: Novel Series of Potent Glucokinase Activators Leading to the Discovery of AM-2394.
abstract: Glucokinase (GK) catalyzes the phosphorylation of glucose to glucose-6-phosphate. We present the structure-activity relationships leading to the discovery of AM-2394, a structurally distinct GKA. AM-2394 activates GK with an EC50 of 60 nM, increases the affinity of GK for glucose by approximately 10-fold, exhibits moderate clearance and good oral bioavailability in multiple animal models, and lowers glucose excursion following an oral glucose tolerance test in an ob/ob mouse model of diabetes.
authors.affiliation: Departments of Therapeutic Discovery, Metabolic Disorders, and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Dransfield
authors.affiliation: Departments of Therapeutic Discovery, Metabolic Disorders, and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Vatee
authors.initials: V
authors.lastname: Pattaropong
authors.affiliation: Departments of Therapeutic Discovery, Metabolic Disorders, and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Sujen
authors.initials: S
authors.lastname: Lai
authors.affiliation: Departments of Therapeutic Discovery, Metabolic Disorders, and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Zice
authors.initials: Z
authors.lastname: Fu
authors.affiliation: Departments of Therapeutic Discovery, Metabolic Disorders, and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Todd J
authors.initials: TJ
authors.lastname: Kohn
authors.affiliation: Departments of Therapeutic Discovery, Metabolic Disorders, and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Du
authors.affiliation: Departments of Therapeutic Discovery, Metabolic Disorders, and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Alan
authors.initials: A
authors.lastname: Cheng
authors.affiliation: Departments of Therapeutic Discovery, Metabolic Disorders, and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Yumei
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: Departments of Metabolic Disorders, Comparative Biology and Safety Sciences and Pharmacokinetics and Drug Metabolism, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Renee
authors.initials: R
authors.lastname: Komorowski
authors.affiliation: Departments of Therapeutic Discovery, Metabolic Disorders, and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Lixia
authors.initials: L
authors.lastname: Jin
authors.affiliation: Departments of Therapeutic Discovery, Metabolic Disorders, and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Marion
authors.initials: M
authors.lastname: Conn
authors.affiliation: Departments of Metabolic Disorders, Comparative Biology and Safety Sciences and Pharmacokinetics and Drug Metabolism, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Eric
authors.initials: E
authors.lastname: Tien
authors.affiliation: Array BioPharma Inc. , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Walter E
authors.initials: WE
authors.lastname: DeWolf
authors.affiliation: Array BioPharma Inc. , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Hinklin
authors.affiliation: Array BioPharma Inc. , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Aicher
authors.affiliation: Array BioPharma Inc. , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Kraser
authors.affiliation: Array BioPharma Inc. , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Boyd
authors.affiliation: Array BioPharma Inc. , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Walter C
authors.initials: WC
authors.lastname: Voegtli
authors.affiliation: Array BioPharma Inc. , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Condroski
authors.affiliation: Departments of Metabolic Disorders, Comparative Biology and Safety Sciences and Pharmacokinetics and Drug Metabolism, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Murielle
authors.initials: M
authors.lastname: Veniant-Ellison
authors.affiliation: Departments of Therapeutic Discovery, Metabolic Disorders, and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Julio C
authors.initials: JC
authors.lastname: Medina
authors.affiliation: Departments of Therapeutic Discovery, Metabolic Disorders, and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Houze
authors.affiliation: Departments of Therapeutic Discovery, Metabolic Disorders, and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Peter
authors.initials: P
authors.lastname: Coward
keywords: AM-2394; GKA; Glucokinase activator