Ripasudil

Ripasudil is a highly selective and potent Rho-associated coiled/coil-containing kinase protein (ROCK) inhibitor. Rho-kinase (ROCK) is an effector protein of Rho which binds with Rho to form a Rho/Rho-kinase complex. This complex then regulates many physiological functions including smooth muscle contractions, chemotaxis, neural growth and gene expression. ROCK comes in 2 isoforms: ROCK-1 and ROCK-2 and these two isoforms are distributed widely in our tissues including ocular tissues such as the iris, retina, trabecular meshwork and ciliary muscles. Atypical regulation of ROCK levels is involved in the pathogenesis of diseases such as glaucoma, ocular hypertension, cataracts and other retinal disorders.

Ripasudil acts as very highly selective and potent inhibitor with an IC50 of Ripasudil with ROCK-1 of 0.051 umol/L and with ROCK-2 of 0.019 umol/L. ROCK inhibitors have efficacy in reducing IOP by acting on the trabecular meshwork in the eye directly to increase conventional outflow through the Schlemm’s canal. Ripasudil will inhibit ROCK and induce cytoskeletal changes including the retraction and rounding of cell bodies and cause disruption of actin bundles in this trabecular meshwork. This can reduce the compaction of trabecular meshwork tissue and eventually result in increased aqueous outflow in the eye and reduced resistance to fluid flow.

Thus, Ripasudil is effective by inducing cytoskeletal changes which are depending on ROCK inhibition. Ripasudil decreases IOP by increasing outflow facility along with modulating the behavior of trabecular meshwork cells and Schlemm’s canal endothelial (SCE) cell permeability along with a disruption of the tight junction.

When Ripasudil is used in combination with prostaglandin analogues it results in increased uveoscleral outflow and when used in combination with beta blockers it results in reduced aqueous production.