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.
Peter Ray  1 ,  Jane Wright ,  Julia Adam ,  Sylviane Boucharens ,  Darcey Black ,  Angus R Brown ,  Ola Epemolu ,  Dan Fletcher ,  Margaret Huggett ,  Phil Jones ,  Steven Laats ,  Amanda Lyons ,  Jos de Man ,  Richard Morphy ,  Brad Sherborne ,  Lorcan Sherry ,  Nicole van Straten ,  Paul Westwood ,  Mark York
Affiliations
  • 1. Discovery Research, MSD, Newhouse, Lanarkshire, ML1 5SH Scotland, UK. [email protected]
PMID: 21251828 DOI: 10.1016/j.bmcl.2010.12.104
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.

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