Details

Autor(en) / Beteiligte

• 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
• Man, Jos de
• Morphy, Richard
• Sherborne, Brad
• Sherry, Lorcan
• Straten, Nicole van
• Westwood, Paul
• York, Mark

Titel

Optimisation of 6-substituted isoquinolin-1-amine based ROCK-I inhibitors

Ist Teil von

• Bioorganic & medicinal chemistry letters, 2011-02, Vol.21 (4), p.1084-1088

Ort / Verlag

Amsterdam: Elsevier Ltd

Erscheinungsjahr

2011

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.