Sulfonylureido thiazoles as fructose-1,6-bisphosphatase inhibitors for the treatment of type-2 diabetes

Bioorg Med Chem Lett. 2010 Jan 15;20(2):594-9. doi: 10.1016/j.bmcl.2009.11.093. Epub 2009 Nov 22.

Abstract

Sulfonylureido thiazoles were identified from a HTS campaign and optimized through a combination of structure-activity studies, X-ray crystallography and molecular modeling to yield potent inhibitors of fructose-1,6-bisphosphatase. Compound 12 showed favorable ADME properties, for example, F=70%, and a robust 32% glucose reduction in the acute db/db mouse model for Type-2 diabetes.

MeSH terms

  • Animals
  • Binding Sites
  • Crystallography, X-Ray
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Disease Models, Animal
  • Fructose-Bisphosphatase / antagonists & inhibitors*
  • Fructose-Bisphosphatase / metabolism
  • High-Throughput Screening Assays
  • Humans
  • Hypoglycemic Agents / chemical synthesis
  • Hypoglycemic Agents / chemistry*
  • Hypoglycemic Agents / pharmacokinetics
  • Mice
  • Structure-Activity Relationship
  • Sulfonylurea Compounds / chemical synthesis
  • Sulfonylurea Compounds / chemistry*
  • Sulfonylurea Compounds / pharmacokinetics
  • Thiazoles / chemical synthesis
  • Thiazoles / chemistry*
  • Thiazoles / pharmacokinetics
  • Thiazoles / pharmacology

Substances

  • Hypoglycemic Agents
  • Sulfonylurea Compounds
  • Thiazoles
  • Fructose-Bisphosphatase