Discovery of potent and orally active 1,4-disubstituted indazoles as novel allosteric glucokinase activators

Bioorg Med Chem Lett. 2017 Jun 15;27(12):2678-2682. doi: 10.1016/j.bmcl.2017.04.041. Epub 2017 Apr 13.

Abstract

Guided by co-crystal structural information obtained from a different series we were exploring, a scaffold morphing and SBDD approach led to the discovery of the 1,4-disubstituted indazole series as a novel class of GKAs that potently activate GK in enzyme and cell assays. anti-diabetic OGTT efficacy was demonstrated with 29 in a rodent models of type 2 diabetes.

Keywords: 1,4-Disubstituted indazole; Glucokinase activator; OGTT; Structure-based drug design; Type 2 diabetes.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Administration, Oral
  • Allosteric Regulation / drug effects
  • Animals
  • Diabetes Mellitus, Experimental / drug therapy*
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / metabolism
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Enzyme Activators / administration & dosage
  • Enzyme Activators / chemistry
  • Enzyme Activators / pharmacology*
  • Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
  • Ether-A-Go-Go Potassium Channels / metabolism
  • Glucokinase / metabolism*
  • Glucose Tolerance Test
  • Humans
  • Indazoles / administration & dosage
  • Indazoles / chemistry
  • Indazoles / pharmacology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • Models, Molecular
  • Molecular Structure
  • Potassium Channel Blockers / pharmacology
  • Structure-Activity Relationship

Substances

  • Enzyme Activators
  • Ether-A-Go-Go Potassium Channels
  • Indazoles
  • Potassium Channel Blockers
  • Glucokinase