Optimisation of 6-substituted isoquinolin-1-amine based ROCK-I inhibitors

Bioorg Med Chem Lett. 2011 Feb 15;21(4):1084-8. doi: 10.1016/j.bmcl.2010.12.104. Epub 2010 Dec 28.

Abstract

Rho kinase is an important target implicated in a variety of cardiovascular diseases. Herein, we report the optimisation of the fragment derived ATP-competitive ROCK inhibitors 1 and 2 into lead compound 14A. The initial goal of improving ROCK-I potency relative to 1, whilst maintaining a good PK profile, was achieved through removal of the aminoisoquinoline basic centre. Lead 14A was equipotent against both ROCK-I and ROCK-II, showed good in vivo efficacy in the spontaneous hypertensive rat model, and was further optimised to demonstrate the scope for improving selectivity over PKA versus hydroxy Fasudil 3.

MeSH terms

  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / analogs & derivatives
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / therapeutic use
  • Amines / chemical synthesis
  • Amines / chemistry*
  • Amines / therapeutic use
  • Animals
  • Disease Models, Animal
  • Hypertension / drug therapy
  • Isoquinolines / chemistry*
  • Models, Chemical
  • Models, Molecular
  • Piperidines / chemical synthesis
  • Piperidines / chemistry*
  • Piperidines / therapeutic use
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / therapeutic use
  • Quinolones / chemical synthesis
  • Quinolones / chemistry*
  • Quinolones / therapeutic use
  • Rats
  • Structure-Activity Relationship
  • rho-Associated Kinases / antagonists & inhibitors*
  • rho-Associated Kinases / metabolism

Substances

  • Amines
  • Isoquinolines
  • Piperidines
  • Protein Kinase Inhibitors
  • Quinolones
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
  • rho-Associated Kinases
  • isoquinoline
  • fasudil