Optimisation of 6-substituted isoquinolin-1-amine based ROCK-I inhibitors |
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| Authors: | Ray Peter Wright Jane Adam Julia Boucharens Sylviane Black Darcey Brown Angus R Epemolu Ola Fletcher Dan Huggett Margaret Jones Phil Laats Steven Lyons Amanda de Man Jos Morphy Richard Sherborne Brad Sherry Lorcan Straten Nicole van Westwood Paul York Mark |
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| Institution: | Discovery Research, MSD, Newhouse, Lanarkshire, ML1 5SH Scotland, UK |
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| 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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| Keywords: | Rho kinase ROCK-I ROCK-II Serine-threonine kinase Inhibitor Optimisation |
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