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Löhn, M.* ; Plettenburg, O.* ; Ivashchenko, Y.* ; Kannt, A.* ; Hofmeister, A.* ; Kadereit, D.* ; Schaefer, M.* ; Linz, W.* ; Kohlmann, M.* ; Herbert, J.M.* ; Janiak, P.* ; O'Connor, S.E.* ; Ruetten, H.*

Pharmacological characterization of SAR407899, a novel rho-kinase inhibitor.

Hypertension 54, 676-683 (2009)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Antihypertensive Therapy ; Arterial Hypertension ; Blood Pressure ; Cardiovascular Diseases ; Rho Kinase ; Vascular Smooth Muscle
Language english
Publication Year 2009
HGF-reported in Year 2009
ISSN (print) / ISBN 0194-911x
e-ISSN 1524-4563
Journal Hypertension
Quellenangaben Volume: 54, Issue: 3, Pages: 676-683 Article Number: , Supplement: ,
Publisher Lippincott Williams & Wilkins
Reviewing status Peer reviewed
Institute(s) Institute of Medicinal Chemistry (IMC)
POF-Topic(s) 30203 - Molecular Targets and Therapies
Research field(s) Enabling and Novel Technologies
PSP Element(s) G-506300-001
PubMed ID 19597037
DOI 10.1161/HYPERTENSIONAHA.109.134353
Scopus ID 70349235617
Erfassungsdatum 2009-09-09
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