Pharmacological Characterization of SAR407899, a Novel Rho-Kinase Inhibitor

authored by

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

Abstract

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.

External Organisation(s)

Sanofi-Aventis Deutschland GmbH
Sanofi-Aventis France

Type

Article

Journal

Hypertension

Volume

54

Pages

676-683

No. of pages

8

ISSN

0194-911X

Publication date

09.2009

Publication status

Published

Peer reviewed

Yes

ASJC Scopus subject areas

Internal Medicine

Sustainable Development Goals

SDG 3 - Good Health and Well-being

Electronic version(s)

https://doi.org/10.1161/HYPERTENSIONAHA.109.134353 (Access: Open)