Pharmacological Characterization of SAR407899, a Novel Rho-Kinase Inhibitor

被引:75
作者
Loehn, Matthias [1 ]
Plettenburg, Oliver
Ivashchenko, Yuri
Kannt, Aimo
Hofmeister, Armin
Kadereit, Dieter
Schaefer, Matthias
Linz, Wolfgang
Kohlmann, Markus
Herbert, Jean-Marc [3 ]
Janiak, Philip [2 ]
O'Connor, Stephen E. [2 ]
Ruetten, Hartmut
机构
[1] Sanofi Aventis, TD CV Pharmacol, Res & Dev, D-65926 Frankfurt, Germany
[2] Sanofi Aventis, Res & Dev, Chilly Mazarin, France
[3] Sanofi Aventis, Res & Dev, Toulouse, France
关键词
arterial hypertension; Rho kinase; vascular smooth muscle; antihypertensive therapy; blood pressure; cardiovascular diseases; POTENTIAL THERAPEUTIC TARGET; NITRIC-OXIDE SYNTHASE; PROTEIN-KINASE; STABLE ANGINA; DOUBLE-BLIND; FASUDIL; PHOSPHORYLATION; INVOLVEMENT; MECHANISM;
D O I
10.1161/HYPERTENSIONAHA.109.134353
中图分类号
R6 [外科学];
学科分类号
1002 ; 100210 ;
摘要
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 approximate to 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. (Hypertension. 2009;54:676-683.)
引用
收藏
页码:676 / 683
页数:8
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