ROCK inhibitors 4: Structure-activity relationship studies of 7-azaindole-based rho kinase (ROCK) inhibitors

Bioorg Med Chem Lett. 2021 Feb 1:33:127721. doi: 10.1016/j.bmcl.2020.127721. Epub 2020 Nov 28.

Abstract

Rho kinase (ROCK) inhibitors are of therapeutic value for the treatment of disorders such as hypertension and glaucoma, and potentially of wider use against diseases such as cancer and multiple sclerosis. We previously reported a series of potent and selective ROCK inhibitors based on a substituted 7-azaindole scaffold. Here we extend the SAR exploration of the 7-azaindole series to identify leads for further evaluation. New compounds such as 16, 17, 19, 21 and 22 showed excellent ROCK potency and protein kinase A (PKA) selectivity, combined with microsome and hepatocyte stability.

Keywords: 7-Azaindole; Rho kinase (ROCK); Thiazole; protein kinase A (PKA).

MeSH terms

  • Animals
  • Dose-Response Relationship, Drug
  • Humans
  • Indoles / chemical synthesis
  • Indoles / chemistry
  • Indoles / pharmacology*
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Rats
  • Structure-Activity Relationship
  • rho-Associated Kinases / antagonists & inhibitors*
  • rho-Associated Kinases / metabolism

Substances

  • 7-azaindole dimer
  • Indoles
  • Protein Kinase Inhibitors
  • ROCK1 protein, human
  • rho-Associated Kinases