Discovery and preclinical development of AR453588 as an anti-diabetic glucokinase activator

  • Bioorg Med Chem. 2020 Jan 1;28(1):115232. doi: 10.1016/j.bmc.2019.115232.
Ronald J Hinklin  1 ,  Brian R Baer  2 ,  Steven A Boyd  2 ,  Mark D Chicarelli  2 ,  Kevin R Condroski  2 ,  Walter E DeWolf Jr  2 ,  John Fischer  2 ,  Michele Frank  2 ,  Gary P Hingorani  2 ,  Patrice A Lee  2 ,  Nickolas A Neitzel  2 ,  Scott A Pratt  2 ,  Ajay Singh  2 ,  Francis X Sullivan  2 ,  Timothy Turner  2 ,  Walter C Voegtli  2 ,  Eli M Wallace  2 ,  Lance Williams  2 ,  Thomas D Aicher  2
Affiliations
  • 1. Array BioPharma Inc., 3200 Walnut St., Boulder, CO 80301, United States. Electronic address: [email protected].
  • 2. Array BioPharma Inc., 3200 Walnut St., Boulder, CO 80301, United States.
PMID: 31818630 DOI: 10.1016/j.bmc.2019.115232
Abstract

Glucose flux through Glucokinase (GK) controls Insulin release from the pancreas in response to high levels of glucose. Flux through GK is also responsible for reducing hepatic glucose output. Since many individuals with type 2 diabetes appear to have an inadequacy or defect in one or both of these processes, identifying compounds that can activate GK could provide a therapeutic benefit. Herein we report the further structure activity studies of a novel series of Glucokinase activators (GKA). These studies led to the identification of pyridine 72 as a potent GKA that lowered post-prandial glucose in normal C57BL/6J mice, and after 14d dosing in ob/ob mice.

Keywords
Diabetes; Glucokinase; Glucokinase activator; OGTT; S(0.5); Structure-aided design; Structure-based design; Type II diabetes; V(max); ob/ob mouse.
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