Novel Inhibitor of Rho Kinase 2013

Abstract

The arising critical implications of Rho kinase signaling in cardiovascular diseases have been attracting attention in the pharmacological potential of Rho kinase inhibitors.

We identified a novel inhibitor of Rho kinase (2-(1H-indazole-5-yl)amino-4-methoxy-6-piperazino triazine; DW 1865) and characterized its effects in biochemical, cellular, tissue and animal based assays. DW 1865 potently inhibited the kinase activity of both Rho kinase 1 and Rho kinase 2 in vitro, and behaved as an ATP-competitive inhibitor.


Interestingly, DW1865 was 10 times more potent in inhibiting Rho kinase activities than fasudil as a selective Rho kinase inhibitor.


The activity of DW1865 was shown to be highly selective for Rho kinase in the panel assay of 13 other kinases.


In the isolated vascular tissue study,
DW1865 exerted vasorelaxation in phenylephrine- or
5-hydroxytriptamine-induced contraction in a concentration-dependent manner manner.


In spontaneously hypertensive rats, administration of DW1865 caused a significant and dose-related reduction in blood pressure. Furthermore, DW1865 blocked angiotensin II-induced stress fiber formation and cellular hypertrophy in rat heart-derived H9c2 cells.


Taken together, these results suggest that DW1865 is a highly selective and potent Rho kinase inhibitor that will alleviate the pathophysiological actions of Rho kinase such as stress fiber formation, cellular hypertrophy, and hypertension.

 

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Graphical abstract

Keywords

• Rho kinase;
• Hypertrophy;
• Hypertension;
• Cardiovascular effect