An emerging treatment option for glaucoma: Rho kinase inhibitors

Rho kinase (ROCK) inhibitors are a novel potential class of glaucoma therapeutics with multiple compounds currently in Phase II and III US Food and Drug Administration trials in the United States. These selective agents work by relaxing the trabecular meshwork through inhibition of the actin cytoskeleton contractile tone of smooth muscle. This results in increased aqueous outflow directly through the trabecular meshwork, achieving lower intraocular pressures in a range similar to prostaglandins. There are also animal studies indicating that ROCK inhibitors may improve blood flow to the optic nerve, increase ganglion cell survival, and reduce bleb scarring in glaucoma surgery. Given the multiple beneficial effects for glaucoma patients, ROCK inhibitors are certainly a highly anticipated emerging treatment option for glaucoma.

[1]  D. Epstein,et al.  Effects of cholesterol-lowering statins on the aqueous humor outflow pathway. , 2005, Investigative ophthalmology & visual science.

[2]  Makoto Nakamura,et al.  A novel ROCK inhibitor, Y-39983, promotes regeneration of crushed axons of retinal ganglion cells into the optic nerve of adult cats , 2007, Experimental Neurology.

[3]  H. Jampel,et al.  Novel glaucoma procedures: a report by the American Academy of Ophthalmology. , 2011, Ophthalmology.

[4]  D. Rice,et al.  Decreased intraocular pressure in mice following either pharmacological or genetic inhibition of ROCK. , 2009, Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics.

[5]  S. S. Agrawal,et al.  Comparative efficacy of pilocarpine, timolol and latanoprost in experimental models of glaucoma. , 2007, Methods and findings in experimental and clinical pharmacology.

[6]  T. Wecker,et al.  Effects of TGF-β2 on cadherins and β-catenin in human trabecular meshwork cells. , 2013, Investigative ophthalmology & visual science.

[7]  R. Lee,et al.  Aqueous Humor Dynamics: A Review , 2010, The open ophthalmology journal.

[8]  K. Itoh,et al.  Overexpression of small GTP-binding protein RhoA promotes invasion of tumor cells. , 1999, Cancer research.

[9]  L. Moons,et al.  MMPs in the trabecular meshwork: promising targets for future glaucoma therapies? , 2013, Investigative ophthalmology & visual science.

[10]  P. Kaufman,et al.  Cytoskeletal involvement in the regulation of aqueous humor outflow. , 2000, Investigative ophthalmology & visual science.

[11]  H. Thieme,et al.  Effects of ML-7 and Y-27632 on carbachol- and endothelin-1-induced contraction of bovine trabecular meshwork. , 2005, Experimental eye research.

[12]  M. Araie,et al.  Intraocular pressure-lowering effects and safety of topical administration of a selective ROCK inhibitor, SNJ-1656, in healthy volunteers. , 2008, Archives of ophthalmology.

[13]  M. Johnstone,et al.  Pulsatile flow into the aqueous veins: Manifestations in normal and glaucomatous eyes , 2011, Experimental eye research.

[14]  T. Schroeter,et al.  Rho-kinase inhibitors as therapeutics: from pan inhibition to isoform selectivity , 2009, Cellular and Molecular Life Sciences.

[15]  K. Fujisawa,et al.  The small GTP‐binding protein Rho binds to and activates a 160 kDa Ser/Thr protein kinase homologous to myotonic dystrophy kinase. , 1996, The EMBO journal.

[16]  Bill Bynum,et al.  Lancet , 2015, The Lancet.

[17]  Anne J. Ridley,et al.  ROCKs: multifunctional kinases in cell behaviour , 2003, Nature Reviews Molecular Cell Biology.

[18]  Paul P. Lee,et al.  An assessment of the health and economic burdens of glaucoma. , 2011, American journal of ophthalmology.

[19]  D. Epstein,et al.  Elevated Levels of RhoA in the Optic Nerve Head of Human Eyes With Glaucoma , 2012, Journal of glaucoma.

[20]  D. Hartshorne,et al.  Rho-associated Kinase of Chicken Gizzard Smooth Muscle* , 1999, The Journal of Biological Chemistry.

[21]  T. Oka,et al.  Reduction of intraocular pressure by topical administration of an inhibitor of the Rho-associated protein kinase , 2001, Current eye research.

[22]  P. Kaufman,et al.  Changes in aqueous humor dynamics with age and glaucoma , 2005, Progress in Retinal and Eye Research.

[23]  S. Semus,et al.  Discovery of aminofurazan-azabenzimidazoles as inhibitors of Rho-kinase with high kinase selectivity and antihypertensive activity. , 2007, Journal of medicinal chemistry.

[24]  E. Stefánsson,et al.  The impact of ocular blood flow in glaucoma , 2002, Progress in Retinal and Eye Research.

[25]  H. Hidaka,et al.  Development of specific Rho-kinase inhibitors and their clinical application. , 2005, Biochimica et biophysica acta.

[26]  Maho Shibata,et al.  Effects of fasudil, a Rho-associated protein kinase inhibitor, on optic nerve head blood flow in rabbits. , 2011, Investigative ophthalmology & visual science.

[27]  K. Kaibuchi,et al.  The COOH Terminus of Rho-kinase Negatively Regulates Rho-kinase Activity* , 1999, The Journal of Biological Chemistry.

[28]  H. Hidaka,et al.  The Effect of the Rho-Associated Protein Kinase Inhibitor, HA-1077, in the Rabbit Ocular Hypertension Model Induced by Water Loading , 2009, Current eye research.

[29]  M. Robinson,et al.  Novel ocular antihypertensive compounds in clinical trials , 2011, Clinical ophthalmology.

[30]  M. Araie,et al.  Phase 2 randomized clinical study of a Rho kinase inhibitor, K-115, in primary open-angle glaucoma and ocular hypertension. , 2013, American journal of ophthalmology.

[31]  X. Q. Chen,et al.  The p160 RhoA-binding kinase ROK alpha is a member of a kinase family and is involved in the reorganization of the cytoskeleton , 1996, Molecular and cellular biology.

[32]  Y. Kitaoka,et al.  Involvement of RhoA and possible neuroprotective effect of fasudil, a Rho kinase inhibitor, in NMDA-induced neurotoxicity in the rat retina , 2004, Brain Research.

[33]  N. Gupta,et al.  Latanoprost Stimulates Ocular Lymphatic Drainage: An In Vivo Nanotracer Study. , 2013, Translational vision science & technology.

[34]  Donald L Budenz,et al.  Prevalence of glaucoma in an urban West African population: the Tema Eye Survey. , 2011, JAMA ophthalmology.

[35]  S. Offermanns,et al.  Rho/Rho-kinase mediated signaling in physiology and pathophysiology , 2002, Journal of Molecular Medicine.

[36]  M. Inatani,et al.  Effects of topical administration of y-39983, a selective rho-associated protein kinase inhibitor, on ocular tissues in rabbits and monkeys. , 2007, Investigative ophthalmology & visual science.

[37]  H. Quigley Number of people with glaucoma worldwide. , 1996, The British journal of ophthalmology.

[38]  M. Araie,et al.  Potential role of Rho-associated protein kinase inhibitor Y-27632 in glaucoma filtration surgery. , 2007, Investigative ophthalmology & visual science.

[39]  M. Morales i Ballús,et al.  The number of people with glaucoma worldwide in 2010 and 2020 , 2006 .

[40]  L. Lim,et al.  A Novel Serine/Threonine Kinase Binding the Ras-related RhoA GTPase Which Translocates the Kinase to Peripheral Membranes (*) , 1995, The Journal of Biological Chemistry.

[41]  D. Epstein,et al.  Acto-myosin drug effects and aqueous outflow function. , 1999, Investigative ophthalmology & visual science.

[42]  K. Nakao,et al.  ROCK‐I and ROCK‐II, two isoforms of Rho‐associated coiled‐coil forming protein serine/threonine kinase in mice , 1996, FEBS letters.

[43]  T. Acott,et al.  The Juxtacanalicular Region of Ocular Trabecular Meshwork: A Tissue with a Unique Extracellular Matrix and Specialized Function. , 2013, Journal of ocular biology.

[44]  Ruikang K. Wang,et al.  Pulsatile motion of the trabecular meshwork in healthy human subjects quantified by phase-sensitive optical coherence tomography. , 2013, Biomedical optics express.

[45]  J. Liao,et al.  Rho Kinase (ROCK) Inhibitors , 2007, Journal of cardiovascular pharmacology.

[46]  Robert N. Weinreb,et al.  Ophthalmic drug discovery: novel targets and mechanisms for retinal diseases and glaucoma , 2012, Nature Reviews Drug Discovery.

[47]  E. E. Hartmann,et al.  The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. , 2002, Archives of ophthalmology.

[48]  W. Feuer,et al.  Treatment outcomes in the Tube Versus Trabeculectomy (TVT) study after five years of follow-up. , 2012, American journal of ophthalmology.

[49]  P. Lograsso,et al.  Chroman-3-amides as potent Rho kinase inhibitors. , 2008, Bioorganic & medicinal chemistry letters.

[50]  Mark Johnson,et al.  'What controls aqueous humour outflow resistance?'. , 2006, Experimental eye research.

[51]  K. Kaibuchi,et al.  Rho-Rho-kinase pathway in smooth muscle contraction and cytoskeletal reorganization of non-muscle cells. , 2001, Trends in pharmacological sciences.

[52]  T. Freddo,et al.  The mechanism of increasing outflow facility by rho-kinase inhibition with Y-27632 in bovine eyes. , 2006, Experimental eye research.

[53]  L. Bourguignon,et al.  Rho-kinase (ROK) promotes CD44v(3,8-10)-ankyrin interaction and tumor cell migration in metastatic breast cancer cells. , 1999, Cell motility and the cytoskeleton.

[54]  J. Fredberg,et al.  Mechanical responsiveness of the endothelial cell of Schlemm's canal: scope, variability and its potential role in controlling aqueous humour outflow , 2012, Journal of The Royal Society Interface.

[55]  R. Maddala,et al.  Novel molecular insights into RhoA GTPase-induced resistance to aqueous humor outflow through the trabecular meshwork. , 2008, American journal of physiology. Cell physiology.

[56]  Shuh Narumiya,et al.  Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension , 1997, Nature.

[57]  D. Epstein,et al.  Expression of dominant negative Rho-binding domain of Rho-kinase in organ cultured human eye anterior segments increases aqueous humor outflow. , 2005, Molecular vision.

[58]  H. Jampel,et al.  Laser trabeculoplasty for open-angle glaucoma: a report by the american academy of ophthalmology. , 2011, Ophthalmology.

[59]  M. Cordeiro,et al.  Clinical Options for the Reduction of Elevated Intraocular Pressure , 2012, Ophthalmology and eye diseases.

[60]  P. Kaufman,et al.  The effect of C3 transgene expression on actin and cellular adhesions in cultured human trabecular meshwork cells and on outflow facility in organ cultured monkey eyes. , 2005, Molecular vision.

[61]  J. Whitson,et al.  Management of Glaucoma: Focus on Pharmacological Therapy , 2005, Drugs & Aging.

[62]  S. Narumiya,et al.  Effects of rho-associated protein kinase inhibitor Y-27632 on intraocular pressure and outflow facility. , 2001, Investigative ophthalmology & visual science.

[63]  M. Araie,et al.  Phase 1 clinical trials of a selective Rho kinase inhibitor, K-115. , 2013, JAMA ophthalmology.

[64]  G. Schlunck,et al.  Contractility as a prerequisite for TGF-beta-induced myofibroblast transdifferentiation in human tenon fibroblasts. , 2006, Investigative ophthalmology & visual science.

[65]  H. Tanihara,et al.  Effects of Y-39983, a Selective Rho-Associated Protein Kinase Inhibitor, on Blood Flow in Optic Nerve Head in Rabbits and Axonal Regeneration of Retinal Ganglion Cells in Rats , 2011, Current eye research.

[66]  D. Epstein,et al.  Rho GTPase/Rho Kinase Inhibition as a Novel Target for the Treatment of Glaucoma , 2012, BioDrugs.

[67]  H. Hidaka,et al.  The Effect of the H-1152P, a Potent Rho-Associated Coiled Coil-Formed Protein Kinase Inhibitor, in Rabbit Normal and Ocular Hypertensive Eyes , 2009, Current eye research.

[68]  D. Epstein,et al.  Modulation of aqueous humor outflow facility by the Rho kinase-specific inhibitor Y-27632. , 2001, Investigative ophthalmology & visual science.

[69]  S. Salomone,et al.  Pharmacological management of ocular hypertension: current approaches and future prospective. , 2013, Current opinion in pharmacology.

[70]  J. McLaren,et al.  Circadian variation of aqueous humor dynamics in older healthy adults. , 2013, Investigative ophthalmology & visual science.

[71]  M. S. Hansen,et al.  The effect of Rho-associated kinase inhibition on the ocular penetration of timolol maleate. , 2013, Investigative ophthalmology & visual science.

[72]  P. Lichter,et al.  Intraocular pressure control and long-term visual field loss in the Collaborative Initial Glaucoma Treatment Study. , 2011, Ophthalmology.

[73]  H. Quigley,et al.  The number of people with glaucoma worldwide in 2010 and 2020 , 2006, British Journal of Ophthalmology.