Discovery of aminofurazan-azabenzimidazoles as inhibitors of Rho-kinase with high kinase selectivity and antihypertensive activity

J Med Chem. 2007 Jan 11;50(1):2-5. doi: 10.1021/jm060873p.

Abstract

The discovery, proposed binding mode, and optimization of a novel class of Rho-kinase inhibitors are presented. Appropriate substitution on the 6-position of the azabenzimidazole core provided subnanomolar enzyme potency in vitro while dramatically improving selectivity over a panel of other kinases. Pharmacokinetic data was obtained for the most potent and selective examples and one (6n) has been shown to lower blood pressure in a rat model of hypertension.

MeSH terms

  • Animals
  • Antihypertensive Agents / chemical synthesis*
  • Antihypertensive Agents / pharmacokinetics
  • Antihypertensive Agents / pharmacology
  • Aorta / drug effects
  • Aorta / physiology
  • Benzimidazoles / chemical synthesis*
  • Benzimidazoles / pharmacokinetics
  • Benzimidazoles / pharmacology
  • Blood Pressure / drug effects
  • In Vitro Techniques
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
  • Models, Molecular
  • Muscle Contraction / drug effects
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / physiology
  • Oxadiazoles / chemical synthesis*
  • Oxadiazoles / pharmacokinetics
  • Oxadiazoles / pharmacology
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Rats
  • Rats, Inbred SHR
  • Structure-Activity Relationship
  • rho-Associated Kinases

Substances

  • Antihypertensive Agents
  • Benzimidazoles
  • Intracellular Signaling Peptides and Proteins
  • Oxadiazoles
  • Protein-Serine-Threonine Kinases
  • rho-Associated Kinases