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Discovery of novel inhibitors for the treatment of glaucoma.

ABSTRACT: Glaucoma is a neurodegenerative disease with heterogeneous causes that result in retinal ganglionic cell (RGC) death. The discovery of ocular antihypertensives has shifted glaucoma therapy, largely, from surgery to medical intervention. Indeed, several intraocular pressure (IOP)-lowering drugs, with different mechanisms of action and RGC protective property, have been developed.In this review, the authors discuss the main new class of kinase inhibitors used as glaucoma treatments, which lower IOP by enhancing drainage and/or lowering production of aqueous humor. The authors include novel inhibitors under preclinical evaluation and investigation for their anti-glaucoma treatment. Additionally, the authors look at treatments that are in clinics now and which may be available in the near future.Treatment of glaucoma remains challenging because the exact cause is yet to be delineated. Neuroprotection to the optic nerve head is undisputable. The novel Rho-associated kinase inhibitors have the capacity to lower IOP and provide optic nerve and RGC protection. In particular, the S-isomer of roscovitine has the capacity to lower IOP and provide neuroprotection. Combinations of selected drugs, which can provide maximal and sustained IOP-lowering effects as well as neuroprotection, are paramount to the prevention of glaucoma progression. In the near future, microRNA intervention may be considered as a potential therapeutic target.

SUBMITTER: Cholkar K

PROVIDER: S-EPMC4589152 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Discovery of novel inhibitors for the treatment of glaucoma.

Cholkar Kishore K Trinh Hoang M HM Pal Dhananjay D Mitra Ashim K AK

Expert opinion on drug discovery 20150109 3

<h4>Introduction</h4>Glaucoma is a neurodegenerative disease with heterogeneous causes that result in retinal ganglionic cell (RGC) death. The discovery of ocular antihypertensives has shifted glaucoma therapy, largely, from surgery to medical intervention. Indeed, several intraocular pressure (IOP)-lowering drugs, with different mechanisms of action and RGC protective property, have been developed.<h4>Areas covered</h4>In this review, the authors discuss the main new class of kinase inhibitors ...[more]

PMID: 25575654

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Project description:In an elegant example of bench-to-bedside research, a hypothesis that cells in the outflow pathway actively regulate conventional outflow resistance was proposed in the 1990s and systematically pursued, exposing novel cellular and molecular mechanisms of intraocular pressure (IOP) regulation. The critical discovery that pharmacologic manipulation of the cytoskeleton of outflow pathway cells decreased outflow resistance placed a spotlight on the Rho kinase pathway that was known to regulate the cytoskeleton. Ultimately, a search for Rho kinase inhibitors led to the discovery of several molecules of therapeutic interest, leaving us today with 2 new ocular hypotensive agents approved for clinical use: ripasudil in Japan and netarsudil in the United States. These represent members of the first new class of clinically useful ocular hypotensive agents since the US Food and Drug Administration approval of latanoprost in 1996. The development of Rho kinase inhibitors as a class of medications to lower IOP in patients with glaucoma and ocular hypertension represents a triumph in translational research. Rho kinase inhibitors are effective alone or when combined with other known ocular hypotensive medications. They also offer the possibility of neuroprotective activity, a favorable impact on ocular blood flow, and even an antifibrotic effect that may prove useful in conventional glaucoma surgery. Local adverse effects, however, including conjunctival hyperemia, subconjunctival hemorrhages, and cornea verticillata, are common. Development of Rho kinase inhibitors targeted to the cells of the outflow pathway and the retina may allow these agents to have even greater clinical impact. The objectives of this review are to describe the basic science underlying the development of Rho kinase inhibitors as a therapy to lower IOP and to summarize the results of the clinical studies reported to date. The neuroprotective and vasoactive properties of Rho kinase inhibitors, as well as the antifibrotic properties, of these agents are reviewed in the context of their possible role in the medical and surgical treatment of glaucoma.

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Discovery of novel inhibitors for the treatment of glaucoma.

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Discovery of novel inhibitors for the treatment of glaucoma.

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