Novel Series of Potent Glucokinase Activators Leading to the Discovery of AM-2394.

Autor:	Dransfield PJ; Departments of Therapeutic Discovery, Metabolic Disorders, and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States., Pattaropong V; Departments of Therapeutic Discovery, Metabolic Disorders, and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States., Lai S; Departments of Therapeutic Discovery, Metabolic Disorders, and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States., Fu Z; Departments of Therapeutic Discovery, Metabolic Disorders, and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States., Kohn TJ; Departments of Therapeutic Discovery, Metabolic Disorders, and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States., Du X; Departments of Therapeutic Discovery, Metabolic Disorders, and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States., Cheng A; Departments of Therapeutic Discovery, Metabolic Disorders, and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States., Xiong Y; Departments of Therapeutic Discovery, Metabolic Disorders, and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States., Komorowski R; 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., Jin L; Departments of Therapeutic Discovery, Metabolic Disorders, and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States., Conn M; Departments of Therapeutic Discovery, Metabolic Disorders, and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States., Tien E; 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., DeWolf WE Jr; Array BioPharma Inc. , 3200 Walnut Street, Boulder, Colorado 80301, United States., Hinklin RJ; Array BioPharma Inc. , 3200 Walnut Street, Boulder, Colorado 80301, United States., Aicher TD; Array BioPharma Inc. , 3200 Walnut Street, Boulder, Colorado 80301, United States., Kraser CF; Array BioPharma Inc. , 3200 Walnut Street, Boulder, Colorado 80301, United States., Boyd SA; Array BioPharma Inc. , 3200 Walnut Street, Boulder, Colorado 80301, United States., Voegtli WC; Array BioPharma Inc. , 3200 Walnut Street, Boulder, Colorado 80301, United States., Condroski KR; Array BioPharma Inc. , 3200 Walnut Street, Boulder, Colorado 80301, United States., Veniant-Ellison M; 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., Medina JC; Departments of Therapeutic Discovery, Metabolic Disorders, and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States., Houze J; Departments of Therapeutic Discovery, Metabolic Disorders, and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States., Coward P; Departments of Therapeutic Discovery, Metabolic Disorders, and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
Jazyk:	angličtina
Zdroj:	ACS medicinal chemistry letters [ACS Med Chem Lett] 2016 May 23; Vol. 7 (7), pp. 714-8. Date of Electronic Publication: 2016 May 23 (Print Publication: 2016).
DOI:	10.1021/acsmedchemlett.6b00140
Abstrakt:	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.
Databáze:	MEDLINE
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