Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
1362168 | Bioorganic & Medicinal Chemistry Letters | 2011 | 5 Pages |
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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Authors
Peter Ray, 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,