2. Academic Validation
  3. Optimisation of 6-substituted isoquinolin-1-amine based ROCK-I inhibitors

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

Affiliation

  • 1 Discovery Research, MSD, Newhouse, Lanarkshire, ML1 5SH Scotland, UK. p.ray@btinternet.com
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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