Rho Kinase (ROCK) Inhibitors and Their Therapeutic Potential

Abstract

Rho kinases (ROCKs) belong to the serine-threonine family, the inhibition of which affects the function of many downstream substrates. As such, ROCK inhibitors have potential therapeutic applicability in a wide variety of pathological conditions including asthma, cancer, erectile dysfunction, glaucoma, insulin resistance, kidney failure, neuronal degeneration, and osteoporosis. To date, two ROCK inhibitors have been approved for clinical use in Japan (fasudil and ripasudil) and one in China (fasudil). In 1995 fasudil was approved for the treatment of cerebral vasospasm, and more recently, ripasudil was approved for the treatment of glaucoma in 2014. In this Perspective, we present a comprehensive review of the physiological and biological functions for ROCK, the properties and development of over 170 ROCK inhibitors as well as their therapeutic potential, the current status, and future considerations.

Podocytes and the actin cytoskeleton as a feasible therapeutic target

“…ROCK is a major downstream effector of RhoA (18,19), and inhibitors like Fasudil are approved for clinical use outside the US to treat pulmonary hypertension by attenuating vascular smooth muscle contraction (24,25). ROCK inhibitors, such as Fasudil, Y27632, SAR407899 and statin, have been shown to attenuate proteinuria and interstitial fibrosis in many (rodent) models of diabetic nephropathy (26,27), 5/6 nephrectomy (28), nephrotoxic nephritis (29), UUO obstruction (30,31), and ischemia reperfusion injury (32).…”

“…Another characteristic that distinguishes dynamin from canonical small GTPases is that dynamin directly binds actin filaments (10,40). Dynamin-actin interactions promote GTP-dependent dynamin oligomerization, which releases capping protein gelsolin from the barbed ends resulting in the potent actin polymerization from the fast growing barbed ends and focal adhesion maturation (25). The molecular mechanism by which dynamin releases gelsolin from the barbed ends is at present unknown, but fluorescence lifetime imaging microscopy suggests that it requires GTP binding and a major conformational change within dynamin tetramers (40).…”

ROCK inhibitors in ocular disease

“…A summary from last year listed more than 170 different compounds used in various research areas from cancer to respiratory disease [1], and since then the number of substances has only increased. In the case of ocular disease, ripasudil was approved in 2014 for the treatment of glaucoma and ocular hypertension (OHT) [2].…”

“…In the case of ocular disease, ripasudil was approved in 2014 for the treatment of glaucoma and ocular hypertension (OHT) [2]. There are other promising candidates for ocular disease in phase II or phase III clinical trials; however, a number of drugs have also already failed [1,3] (see Table 1). …”

Where Should We Be Looking for the Future of IOP Lowering Drugs? Commentary on "New Therapeutic Targets for Intraocular Pressure Lowering"

“…The most common side effect, similarly to Rhopressa™, was conjunctival hyperemia (74.6% of patients vs 1.9% with placebo), however most cases were mild, transient and had spontaneous resolution [6]. Altough the results seem promising, a combination with latanoprost or timolol might not be possible, since this compound needs bid dosing and it reduces the ocular bioavailability of timolol [7].…”