Investigational Rho Kinase Inhibitors for the Treatment of Glaucoma

Abstract

This review provides a comprehensive update on emerging ROCK inhibitors as an innovative treatment option for lowering intraocular pressure (IOP) in glaucoma and aims to describe the structure, mechanism of action, pharmaceutical characteristics, desirable ocular effects, including side effects for each agent. A literature review was conducted using PubMed, Scopus, clinicaltrials.gov, ARVO journals, Cochrane library and Selleckchem. Databases were searched using “investigational Rho kinase inhibitors,” and “glaucoma” as keywords. In addition to this building block strategy, successive fractions were employed to further refine the results. Of the several ROCK inhibitors discovered, only two drugs are currently approved for glaucoma treatment; Netarsudil in the USA and Ripasudil in Japan and China. We identified and reviewed 15 agents currently in laboratory or clinical trials. These agents lower IOP mainly by decreasing outflow resistance through pharmacologic relaxation of the trabecular meshwork (TM) cells and reducing episcleral venous pressure. They have an optimistic safety profile; however, conjunctival hyperemia, conjunctival hemorrhage, pain on instillation, and corneal verticillata are common. Other properties such as neuroprotection (enhancing optic nerve blood flow and promoting axonal regeneration), anti-fibrotic activity, and endothelial cell proliferation may improve the visual prognosis and surgical outcomes in glaucoma. In addition, these agents have the potential to work synergistically with other topical glaucoma medications.

Rho GTPases in Retinal Vascular Diseases

“…To avoid systemic toxicity, the local manipulation of Rho GTPase signals is desirable. Currently, an ophthalmic solution of a small-molecule ROCK inhibitor, ripasudil hydrochloride hydrate, has been approved for the treatment of glaucoma in Japan and other Asian countries [81,82]. Experimentally, topical ripasudil significantly reduced the retinal thickness, neovascularization, and avascular areas in mouse models of ischemic retinopathy [83,84].…”

Simultaneous Use of ROCK Inhibitors and EP2 Agonists Induces Unexpected Effects on Adipogenesis and the Physical Properties of 3T3-L1 Preadipocytes

“…However, it is known that EP2 receptors are also expressed in 3T3-L1 cells and that they are involved in different intracellular signaling pathways, in which the EP2 receptor is coupled to Gαs, resulting in an increase in cAMP [ 16 ] levels, as compared to those of ROCKs. Interestingly, it is known that both ROCK-is and EP2 agonists function to decrease intraocular pressures (IOPs) in several animal models [ 17 , 18 ], and in fact, among these, ROCK-i, Rip, and the EP2 agonist, OMD, are currently available for treating patients with glaucoma or ocular hypertension [ 19 , 20 ]. In addition, due to the local adverse effects of anti-glaucoma medications, significant attention has been paid to the issue of prostaglandin (PG)-induced peri-orbitopathy, such as the deepening of the upper eyelid sulcus (DUES) [ 21 , 22 ].…”

Acute RhoA/Rho Kinase Inhibition Is Sufficient to Restore Phagocytic Capacity to Retinal Pigment Epithelium Lacking the Engulfment Receptor MerTK

“…Our studies show that RPE phagocytosis due to MerTK deficiency can be rescued simply by manipulating MerTK downstream signaling pathways, bypassing the need for receptor restoration. ROCK inhibitors are already approved in common, long-term use for ocular disease (recently reviewed in [56]). In addition to abolishing phagocytosis, MerTK deficiency in the eye also elicits harmful retinal inflammation, which can be alleviated with the application of anti-inflammatory drugs such as eye drops, which slow retinal degeneration in vivo [57].…”