Discovery of a phenylpyrazole amide ROCK inhibitor as a tool molecule for in vivo studies

Bioorg Med Chem Lett. 2020 Nov 1;30(21):127495. doi: 10.1016/j.bmcl.2020.127495. Epub 2020 Aug 13.

Abstract

Structure-activity relationship optimization on a series of phenylpyrazole amides led to the identification of a dual ROCK1 and ROCK2 inhibitor (25) which demonstrated good potency, kinome selectivity and favorable pharmacokinetic profiles. Compound 25 was selected as a tool molecule for in vivo studies including evaluating hemodynamic effects in telemeterized mice, from which moderate decreases in blood pressure were observed.

Keywords: Dual inhibitor; Phenylpyrazole; ROCK; Rho kinase inhibitor; Telemetry study.

MeSH terms

  • Amides / chemical synthesis
  • Amides / chemistry
  • Amides / pharmacology*
  • Animals
  • Blood Pressure / drug effects
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Mice
  • Models, Molecular
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology*
  • Structure-Activity Relationship
  • rho-Associated Kinases / antagonists & inhibitors*
  • rho-Associated Kinases / metabolism

Substances

  • Amides
  • Protein Kinase Inhibitors
  • Pyrazoles
  • pyrazole
  • ROCK1 protein, human
  • ROCK2 protein, human
  • rho-Associated Kinases