title: Pharmacological characterization of SAR407899, a novel rho-kinase inhibitor.
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 approximately 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 IC(50) 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.
authors: TD CV Pharmacology, Sanofi-Aventis, Industriepark Hoechst, Frankfurt am Main, Frankfurt, Germany. Matthias.loehn@sanofi-aventis.com
authors: Matthias
authors: M
authors: Löhn
authors: Oliver
authors: O
authors: Plettenburg
authors: Yuri
authors: Y
authors: Ivashchenko
authors: Aimo
authors: A
authors: Kannt
authors: Armin
authors: A
authors: Hofmeister
authors: Dieter
authors: D
authors: Kadereit
authors: Matthias
authors: M
authors: Schaefer
authors: Wolfgang
authors: W
authors: Linz
authors: Markus
authors: M
authors: Kohlmann
authors: Jean-Marc
authors: JM
authors: Herbert
authors: Philip
authors: P
authors: Janiak
authors: Stephen E
authors: SE
authors: O'Connor
authors: Hartmut
authors: H
authors: Ruetten
mesh_terms: D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects; D002384:Catalysis / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002633:Chemotaxis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D043263:Myosin-Light-Chain Phosphatase / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017207:Rats, Sprague-Dawley; D022502:Stress Fibers / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D054460:rho-Associated Kinases; D043263:Myosin-Light-Chain Phosphatase