Novel ROCK inhibitors for the treatment of pulmonary arterial hypertension

Bioorg Med Chem Lett. 2014 Oct 15;24(20):4812-7. doi: 10.1016/j.bmcl.2014.09.002. Epub 2014 Sep 6.

Abstract

A novel class of selective inhibitors of ROCK1 and ROCK2 has been identified by structural based drug design. PK/PD experiments using a set of highly selective Rho kinase inhibitors suggest that systemic Rho kinase inhibition is linked to a reversible reduction in lymphocyte counts. These results led to the consideration of topical delivery of these molecules, and to the identification of a lead molecule 7 which shows promising PK and PD in a murine model of pulmonary hypertension after intra-tracheal dosing.

Keywords: Inhibitors; Intra-tracheal dosing; Lymphocyte depletion; Pulmonary arterial hypertension; Rho kinase.

MeSH terms

  • Animals
  • Crystallography, X-Ray
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Humans
  • Hypertension, Pulmonary / drug therapy*
  • Hypertension, Pulmonary / enzymology
  • Hypertension, Pulmonary / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Models, Molecular
  • Molecular Structure
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Rats
  • Rats, Inbred Lew
  • Structure-Activity Relationship
  • rho-Associated Kinases / antagonists & inhibitors*
  • rho-Associated Kinases / metabolism

Substances

  • Protein Kinase Inhibitors
  • rho-Associated Kinases