Newly Synthesized Potent ROCKII Inhibitor Isoquinolinesulfonamide Derivative Remarkably Reduces Intraocular Pressure in Cynomologus Monkey and Rabbit

Abstract

 

Purpose:

 

Recently, ROCK inhibitor had shown that it could be one of the novel candidates of the glaucoma therapy. ROCK inhibitor lowered intraocular pressure by modulating the morphology of the trabecullar meshwork cells which upregulates the aqueous humor outflow facility through the Schlemm’s canal. We have been developing the isoquinolinesulfonamide derivatives as a ROCK inhibitor and reported that H-1152P, one of the derivatives, had potent inhibitory action for ROCKII. Lately we succeeded in synthesizing a new potent ROCKII inhibitor isoquinolinesulfonamide derivative.

 

Methods:

 

The inhibitory effect on ROCKII of this new compound was measured, and the effects on the intraocular pressure were studied by the instillation in normal Cynomologus monkey, New Zealand White rabbit and Dutch belt rabbit.

 

Results:

 

This compound inhibited ROCKII with IC₅₀ value of 18.7 nM, and its instillation remarkably reduced intraocular pressure during several hours in Cymologus monkey (as shown in Fig) and rabbit, These effects on intraocular pressure were dose-dependently.

 

Conclusions:

 

The results indicate the potential use of this newly synthesized compound as an ocular hypotensive agent.  

 

Keywords: intraocular pressure • drug toxicity/drug effects • enzymes/enzyme inhibitors