Design, synthesis, and pharmacological evaluation of benzamide derivatives as glucokinase activators

Bioorg Med Chem. 2012 May 1;20(9):2982-91. doi: 10.1016/j.bmc.2012.03.008. Epub 2012 Mar 8.

Abstract

A series of benzamide derivatives were assembled by using the privileged-fragment-merging (PFM) strategy and their SAR studies as glucokinase activators were described. Compounds 5 and 16b were identified having a suitable balance of potency and activation profile. They showed EC(50) values of 28.3 and 44.8 nM, and activation folds of 2.4 and 2.2, respectively. However, both compounds displayed a minor reduction in plasma glucose levels on imprinting control region (ICR) mice. Unfavorable pharmacokinetic profiles (PK) were also observed on these two compounds.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzamides / blood
  • Benzamides / chemical synthesis*
  • Benzamides / chemistry*
  • Benzamides / pharmacokinetics
  • Benzamides / pharmacology*
  • Biological Availability
  • Drug Design*
  • Enzyme Activation / drug effects
  • Glucokinase / chemistry
  • Glucokinase / metabolism*
  • Hypoglycemic Agents / blood
  • Hypoglycemic Agents / chemical synthesis*
  • Hypoglycemic Agents / pharmacokinetics
  • Hypoglycemic Agents / pharmacology*
  • Mice
  • Mice, Inbred ICR
  • Structure-Activity Relationship
  • Thiazoles / blood
  • Thiazoles / chemical synthesis*
  • Thiazoles / chemistry
  • Thiazoles / pharmacokinetics
  • Thiazoles / pharmacology

Substances

  • (S)-3-(4-((3-fluoropyrrolidin-1-yl)sulfonyl)phenoxy)-5-((3-methylbut-2-en-1-yl)oxy)-N-(thiazol-2-yl)benzamide
  • 3-(4-(cyclopropylsulfonyl)phenoxy)-5-((3-methylbut-2-en-1-yl)oxy)-N-(thiazol-2-yl)benzamide
  • Benzamides
  • Hypoglycemic Agents
  • Thiazoles
  • benzamide
  • Glucokinase