2. Academic Validation
  3. Novel Series of Potent Glucokinase Activators Leading to the Discovery of AM-2394

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

  • ACS Med Chem Lett. 2016 May 23;7(7):714-8. doi: 10.1021/acsmedchemlett.6b00140.
Paul J Dransfield 1,  Vatee Pattaropong 1,  Sujen Lai 1,  Zice Fu 1,  Todd J Kohn 1,  Xiaohui Du 1,  Alan Cheng 1,  Yumei Xiong 1,  Renee Komorowski 2,  Lixia Jin 1,  Marion Conn 1,  Eric Tien 2,  Walter E DeWolf Jr 3,  Ronald J Hinklin 3,  Thomas D Aicher 3,  Christopher F Kraser 3,  Steven A Boyd 3,  Walter C Voegtli 3,  Kevin R Condroski 3,  Murielle Veniant-Ellison 2,  Julio C Medina 1,  Jonathan Houze 1,  Peter Coward 1
Affiliations

Affiliations

  • 1 Departments of Therapeutic Discovery, Metabolic Disorders, and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
  • 2 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.
  • 3 Array BioPharma Inc. , 3200 Walnut Street, Boulder, Colorado 80301, United States.
PMID: 27437083 DOI: 10.1021/acsmedchemlett.6b00140
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.

Keywords

AM-2394; GKA; Glucokinase activator.

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