Design, synthesis and SAR of novel glucokinase activators

Bioorg Med Chem Lett. 2013 Apr 1;23(7):2166-71. doi: 10.1016/j.bmcl.2013.01.093. Epub 2013 Feb 4.

Abstract

Guided by co-crystal structures of compounds 15, 22 and 30, an SBDD approach led to the discovery of the 6-methyl pyridone series as a novel class of GKAs that potently activate GK in enzyme and cell assays. Anti-diabetic OGTT efficacy was demonstrated with 54 in a mouse model of type 2 diabetes.

Publication types

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

MeSH terms

  • Animals
  • Crystallography, X-Ray
  • Diabetes Mellitus, Experimental / drug therapy
  • Diabetes Mellitus, Experimental / enzymology*
  • Disease Models, Animal
  • Drug Design*
  • Enzyme Activation / drug effects
  • Enzyme Activators / administration & dosage
  • Enzyme Activators / chemistry
  • Enzyme Activators / pharmacology*
  • Glucokinase / metabolism*
  • Glucose Tolerance Test
  • Hypoglycemic Agents / administration & dosage
  • Hypoglycemic Agents / chemistry
  • Hypoglycemic Agents / pharmacology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • Models, Molecular
  • Molecular Structure
  • Pyridones / administration & dosage
  • Pyridones / chemistry
  • Pyridones / pharmacology*
  • Structure-Activity Relationship

Substances

  • Enzyme Activators
  • Hypoglycemic Agents
  • Pyridones
  • Glucokinase