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
  • 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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