Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 21, Issue 4, Pages 1084-1088Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2010.12.104
Keywords
Rho kinase; ROCK-I; ROCK-II; Serine-threonine kinase; Inhibitor; Optimisation
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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. (c) 2010 Elsevier Ltd. All rights reserved.
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