Academic Journal
Pharmacological Characterization of SAR407899, a Novel Rho-Kinase Inhibitor
| العنوان: | Pharmacological Characterization of SAR407899, a Novel Rho-Kinase Inhibitor |
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| المؤلفون: | Löhn, Matthias, Plettenburg, Oliver, Ivashchenko, Yuri, Kannt, Aimo, Hofmeister, Armin, Kadereit, Dieter, Schaefer, Matthias, Linz, Wolfgang, Kohlmann, Markus, Herbert, Jean-Marc, Janiak, Philip, O'Connor, Stephen E., Ruetten, Hartmut |
| المصدر: | Hypertension ; volume 54, issue 3, page 676-683 ; ISSN 0194-911X 1524-4563 |
| بيانات النشر: | Ovid Technologies (Wolters Kluwer Health) |
| سنة النشر: | 2009 |
| الوصف: | 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 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1161/hypertensionaha.109.134353 |
| DOI: | 10.1161/HYPERTENSIONAHA.109.134353 |
| الاتاحة: | http://dx.doi.org/10.1161/hypertensionaha.109.134353 https://www.ahajournals.org/doi/full/10.1161/HYPERTENSIONAHA.109.134353 |
| رقم الانضمام: | edsbas.E6998971 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1161/hypertensionaha.109.134353 |
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