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(Hypertension. 2009;54:676.)
© 2009 American Heart Association, Inc.

Original Articles

Pharmacological Characterization of SAR407899, a Novel Rho-Kinase Inhibitor

Matthias Löhn; Oliver Plettenburg; Yuri Ivashchenko; Aimo Kannt; Armin Hofmeister; Dieter Kadereit; Matthias Schaefer; Wolfgang Linz; Markus Kohlmann; Jean-Marc Herbert; Philip Janiak; Stephen E. O'Connor; Hartmut Ruetten

From the Sanofi-Aventis Research and Development (M.L., O.P., Y.I., A.K., A.H., D.K., M.S., W.L., M.K., H.R.), Frankfurt, Germany; Sanofi-Aventis Research and Development (P.J., S.E.O.), Chilly-Mazarin, France; Sanofi-Aventis Research and Development (J.-M.H.), Toulouse, France.

Correspondence to Matthias Löhn, TD CV Pharmacology, Sanofi-Aventis, Industriepark Hoechst, 65926 Frankfurt am Main, Frankfurt, Germany. E-mail Matthias.loehn{at}sanofi-aventis.com

Recent advances in basic and clinical research have identified Rho kinase as an important target potentially implicated in a variety of cardiovascular diseases. Rho kinase is a downstream mediator of RhoA that leads to stress fiber formation, membrane ruffling, smooth muscle contraction, and cell motility. Increased Rho-kinase activity is associated with vasoconstriction and elevated blood pressure. We identified a novel inhibitor of Rho kinase (SAR407899) and characterized its effects in biochemical, cellular, tissue-based, and in vivo assays. SAR407899 is an ATP-competitive Rho-kinase inhibitor, equipotent against human and rat-derived Rho-kinase 2 with inhibition constant values of 36 nM and 41 nM, respectively. It is highly selective in panel of 117 receptor and enzyme targets. SAR407899 is 8-fold more active than fasudil. In vitro, SAR407899 demonstrated concentration-dependent inhibition of Rho-kinase–mediated phosphorylation of myosin phosphatase, thrombin-induced stress fiber formation, platelet-derived growth factor–induced proliferation, and monocyte chemotactic protein-1–stimulated chemotaxis. SAR407899 potently (mean IC₅₀ values: 122 to 280 nM) and species-independently relaxed precontracted isolated arteries of different species and different vascular beds. In vivo, over the dose range 3 to 30 mg/kg PO, SAR407899 lowered blood pressure in a variety of rodent models of arterial hypertension. The antihypertensive effect of SAR407899 was superior to that of fasudil and Y-27632. In conclusion, SAR407899 is a novel and potent selective Rho-kinase inhibitor with promising antihypertensive activity.

Key Words: arterial hypertension • Rho kinase • vascular smooth muscle • antihypertensive therapy • blood pressure • cardiovascular diseases