Discovery, structure-activity relationships, pharmacokinetics, and efficacy of glucokinase activator (2R)-3-cyclopentyl-2-(4-methanesulfonylphenyl)-N-thiazol-2-yl-propionamide (RO0281675)

J Med Chem. 2010 May 13;53(9):3618-25. doi: 10.1021/jm100039a.

Abstract

Glucokinase (GK) is a glucose sensor that couples glucose metabolism to insulin release. The important role of GK in maintaining glucose homeostasis is illustrated in patients with GK mutations. In this publication, identification of the hit molecule 1 and its SAR development, which led to the discovery of potent allosteric GK activators 9a and 21a, is described. Compound 21a (RO0281675) was used to validate the clinical relevance of targeting GK to treat type 2 diabetes.

MeSH terms

  • Animals
  • Blood Glucose
  • Cell Line
  • Cytotoxins
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Dose-Response Relationship, Drug
  • Drug Discovery
  • Glucokinase / drug effects*
  • Humans
  • Hypoglycemic Agents / chemistry*
  • Insulin
  • Male
  • Mice
  • Pharmacokinetics
  • Structure-Activity Relationship
  • Sulfones / chemistry
  • Sulfones / pharmacology*
  • Sulfones / toxicity
  • Thiazoles / chemistry
  • Thiazoles / pharmacology*
  • Thiazoles / toxicity

Substances

  • 3-cyclopentyl-2-(4-methanesulfonylphenyl)-N-thiazol-2-yl-propionamide
  • Blood Glucose
  • Cytotoxins
  • Hypoglycemic Agents
  • Insulin
  • Sulfones
  • Thiazoles
  • Glucokinase