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Current Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Review Article

Rho-kinase (ROCK) Inhibitors - A Neuroprotective Therapeutic Paradigm with a Focus on Ocular Utility

Author(s): Vasudha Abbhi and Poonam Piplani*

Volume 27, Issue 14, 2020

Page: [2222 - 2256] Pages: 35

DOI: 10.2174/0929867325666181031102829

Price: $65

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Abstract

Background: Glaucoma is a progressive optic neuropathy causing visual impairment and Retinal Ganglionic Cells (RGCs) death gradually posing a need for neuroprotective strategies to minimize the loss of RGCs and visual field. It is recognized as a multifactorial disease, Intraocular Pressure (IOP) being the foremost risk factor. ROCK inhibitors have been probed for various possible indications, such as myocardial ischemia, hypertension, kidney diseases. Their role in neuroprotection and neuronal regeneration has been suggested to be of value in the treatment of neurological diseases, like spinal-cord injury, Alzheimer’s disease and multiple sclerosis but recently Rho-associated Kinase inhibitors have been recognized as potential antiglaucoma agents.

Evidence Synthesis: Rho-Kinase is a serine/threonine kinase with a kinase domain which is constitutively active and is involved in the regulation of smooth muscle contraction and stress fibre formation. Two isoforms of Rho-Kinase, ROCK-I (ROCK β) and ROCK-II (ROCK α) have been identified. ROCK II plays a pathophysiological role in glaucoma and hence the inhibitors of ROCK may be beneficial to ameliorate the vision loss. These inhibitors decrease the intraocular pressure in the glaucomatous eye by increasing the aqueous humour outflow through the trabecular meshwork pathway. They also act as anti-scarring agents and hence prevent post-operative scarring after the glaucoma filtration surgery. Their major role involves axon regeneration by increasing the optic nerve blood flow which may be useful in treating the damaged optic neurons. These drugs act directly on the neurons in the central visual pathway, interrupting the RGC apoptosis and therefore serve as a novel pharmacological approach for glaucoma neuroprotection.

Conclusion: Based on the results of high-throughput screening, several Rho kinase inhibitors have been designed and developed comprising of diverse scaffolds exhibiting Rho kinase inhibitory activity from micromolar to subnanomolar ranges. This diversity in the scaffolds with inhibitory potential against the kinase and their SAR development will be intricated in the present review. Ripasudil is the only Rho kinase inhibitor marketed to date for the treatment of glaucoma. Another ROCK inhibitor AR-13324 has recently passed the clinical trials whereas AMA0076, K115, PG324, Y39983 and RKI-983 are still under trials. In view of this, a detailed and updated account of ROCK II inhibitors as the next generation therapeutic agents for glaucoma will be discussed in this review.

Keywords: Glaucoma, intraocular pressure, Rho-Kinase inhibitors, trabecular meshwork, neuroprotection, ripasudil.

[1]
Turkoski, B.B. Glaucoma and glaucoma medications. Orthop. Nurs., 2012, 31(1), 37-41.
[http://dx.doi.org/10.1097/NOR.0b013e31824196a8] [PMID: 22278651]
[2]
Kulkarni, U. Early detection of primary open angle glaucoma: is it happening? J. Clin. Diagn. Res., 2012, 6, 667-670.
[3]
Tham, Y.C.; Li, X.; Wong, T.Y.; Quigley, H.A.; Aung, T.; Cheng, C.Y. Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic review and meta-analysis. Ophthalmology, 2014, 121(11), 2081-2090.
[http://dx.doi.org/10.1016/j.ophtha.2014.05.013] [PMID: 24974815]
[4]
Gupta, N.; Yücel, Y.H. Glaucoma as a neurodegenerative disease. Curr. Opin. Ophthalmol., 2007, 18(2), 110-114.
[http://dx.doi.org/10.1097/ICU.0b013e3280895aea] [PMID: 17301611]
[5]
Wax, M.B.; Tezel, G. Neurobiology of glaucomatous optic neuropathy: diverse cellular events in neurodegeneration and neuroprotection. Mol. Neurobiol., 2002, 26(1), 45-55.
[http://dx.doi.org/10.1385/MN:26:1:045] [PMID: 12392055]
[6]
Nickells, R.W. From ocular hypertension to ganglion cell death: a theoretical sequence of events leading to glaucoma. Can. J. Ophthalmol., 2007, 42(2), 278-287.
[http://dx.doi.org/10.3129/can j ophthalmol.i07-036] [PMID: 17392853]
[7]
Pascale, A.; Drago, F.; Govoni, S. Protecting the retinal neurons from glaucoma: lowering ocular pressure is not enough. Pharmacol. Res., 2012, 66(1), 19-32.
[http://dx.doi.org/10.1016/j.phrs.2012.03.002] [PMID: 22433276]
[8]
Coleman, A.L.; Miglior, S. Risk factors for glaucoma onset and progression. Surv. Ophthalmol., 2008, 53(Suppl. 1), S3-S10.
[http://dx.doi.org/10.1016/j.survophthal.2008.08.006] [PMID: 19038621]
[9]
Coleman, A.L. Glaucoma. Lancet, 1999, 354(9192), 1803-1810.
[http://dx.doi.org/10.1016/S0140-6736(99)04240-3] [PMID: 10577657]
[10]
Agarwal, R.; Gupta, S.K.; Agarwal, P.; Saxena, R.; Agrawal, S.S. Current concepts in the pathophysiology of glaucoma. Indian J. Ophthalmol., 2009, 57(4), 257-266.
[http://dx.doi.org/10.4103/0301-4738.53049] [PMID: 19574692]
[11]
Weinreb, R.N.; Aung, T.; Medeiros, F.A. The pathophysiology and treatment of glaucoma: a review. JAMA, 2014, 311(18), 1901-1911.
[http://dx.doi.org/10.1001/jama.2014.3192] [PMID: 24825645]
[12]
Aslan, M.; Cort, A.; Yucel, I. Oxidative and nitrative stress markers in glaucoma. Free Radic. Biol. Med., 2008, 45(4), 367-376.
[http://dx.doi.org/10.1016/j.freeradbiomed.2008.04.026] [PMID: 18489911]
[13]
Costa, V.P.; Harris, A.; Anderson, D.; Stodtmeister, R.; Cremasco, F.; Kergoat, H.; Lovasik, J.; Stalmans, I.; Zeitz, O.; Lanzl, I.; Gugleta, K.; Schmetterer, L. Ocular perfusion pressure in glaucoma. Acta Ophthalmol., 2014, 92(4), e252-e266.
[http://dx.doi.org/10.1111/aos.12298] [PMID: 24238296]
[14]
Mozaffarieh, M.; Flammer, J. Is there more to glaucoma treatment than lowering IOP? Surv. Ophthalmol., 2007, 52(Suppl. 2), S174-S179.
[http://dx.doi.org/10.1016/j.survophthal.2007.08.013] [PMID: 17998043]
[15]
Crish, S.D.; Calkins, D.J. Neurodegeneration in glaucoma: progression and calcium-dependent intracellular mechanisms. Neuroscience, 2011, 176, 1-11.
[http://dx.doi.org/10.1016/j.neuroscience.2010.12.036] [PMID: 21187126]
[16]
Vieth, M.; Erickson, J.; Wang, J.; Webster, Y.; Mader, M.; Higgs, R.; Watson, I. Kinase inhibitor data modeling and de novo inhibitor design with fragment approaches. J. Med. Chem., 2009, 52(20), 6456-6466.
[http://dx.doi.org/10.1021/jm901147e] [PMID: 19791746]
[17]
McGovern, S.L.; Shoichet, B.K. Kinase inhibitors: not just for kinases anymore. J. Med. Chem., 2003, 46(8), 1478-1483.
[http://dx.doi.org/10.1021/jm020427b] [PMID: 12672248]
[18]
Tamura, M.; Nakao, H.; Yoshizaki, H.; Shiratsuchi, M.; Shigyo, H.; Yamada, H.; Ozawa, T.; Totsuka, J.; Hidaka, H. Development of specific Rho-kinase inhibitors and their clinical application. Biochim. Biophys. Acta, 2005, 1754(1-2), 245-252.
[http://dx.doi.org/10.1016/j.bbapap.2005.06.015] [PMID: 16213195]
[19]
Amano, M.; Fukata, Y.; Kaibuchi, K. Regulation and functions of Rho-associated kinase. Exp. Cell Res., 2000, 261(1), 44-51.
[http://dx.doi.org/10.1006/excr.2000.5046] [PMID: 11082274]
[20]
Olson, M.F. Applications for ROCK kinase inhibition. Curr. Opin. Cell Biol., 2008, 20(2), 242-248.
[http://dx.doi.org/10.1016/j.ceb.2008.01.002] [PMID: 18282695]
[21]
Matsui, T.; Amano, M.; Yamamoto, T.; Chihara, K.; Nakafuku, M.; Ito, M.; Nakano, T.; Okawa, K.; Iwamatsu, A.; Kaibuchi, K. Rho-associated kinase, a novel serine/threonine kinase, as a putative target for small GTP binding protein Rho. EMBO J., 1996, 15(9), 2208-2216.
[http://dx.doi.org/10.1002/j.1460-2075.1996.tb00574.x] [PMID: 8641286]
[22]
LoGrasso, P.V.; Feng, Y. Rho kinase (ROCK) inhibitors and their application to inflammatory disorders. Curr. Top. Med. Chem., 2009, 9(8), 704-723.
[http://dx.doi.org/10.2174/156802609789044452] [PMID: 19689376]
[23]
Liao, J.K.; Seto, M.; Noma, K. Rho kinase (ROCK) inhibitors. J. Cardiovasc. Pharmacol., 2007, 50(1), 17-24.
[http://dx.doi.org/10.1097/FJC.0b013e318070d1bd] [PMID: 17666911]
[24]
Honjo, M.; Tanihara, H. Impact of the clinical use of ROCK inhibitor on the pathogenesis and treatment of glaucoma. Jpn. J. Ophthalmol., 2018, 62(2), 109-126.
[http://dx.doi.org/10.1007/s10384-018-0566-9] [PMID: 29445943]
[25]
Inoue, T.; Tanihara, H. Rho-associated kinase inhibitors: a novel glaucoma therapy. Prog. Retin. Eye Res., 2013, 37, 1-12.
[http://dx.doi.org/10.1016/j.preteyeres.2013.05.002] [PMID: 23770081]
[26]
Nakajima, E.; Nakajima, T.; Minagawa, Y.; Shearer, T.R.; Azuma, M. Contribution of ROCK in contraction of trabecular meshwork: proposed mechanism for regulating aqueous outflow in monkey and human eyes. J. Pharm. Sci., 2005, 94(4), 701-708.
[http://dx.doi.org/10.1002/jps.20285] [PMID: 15682386]
[27]
Rao, P.V.; Deng, P.F.; Kumar, J.; Epstein, D.L. Modulation of aqueous humor outflow facility by the Rho kinase-specific inhibitor Y-27632. Invest. Ophthalmol. Vis. Sci., 2001, 42(5), 1029-1037.
[PMID: 11274082]
[28]
Lu, Z.; Overby, D.R.; Scott, P.A.; Freddo, T.F.; Gong, H. The mechanism of increasing outflow facility by rho-kinase inhibition with Y-27632 in bovine eyes. Exp. Eye Res., 2008, 86(2), 271-281.
[http://dx.doi.org/10.1016/j.exer.2007.10.018] [PMID: 18155193]
[29]
Okumura, N.; Koizumi, N.; Ueno, M.; Sakamoto, Y.; Takahashi, H.; Hirata, K.; Torii, R.; Hamuro, J.; Kinoshita, S. Enhancement of corneal endothelium wound healing by Rho-associated kinase (ROCK) inhibitor eye drops. Br. J. Ophthalmol., 2011, 95(7), 1006-1009.
[http://dx.doi.org/10.1136/bjo.2010.194571] [PMID: 21398412]
[30]
Okumura, N.; Kinoshita, S.; Koizumi, N. Application of rho kinase inhibitors for the treatment of corneal endothelial diseases. J. Ophthalmol., 2017, 20172646904
[http://dx.doi.org/10.1155/2017/2646904] [PMID: 28751979]
[31]
Bond, J.E.; Kokosis, G.; Ren, L.; Selim, M.A.; Bergeron, A.; Levinson, H. Wound contraction is attenuated by fasudil inhibition of Rho-associated kinase. Plast. Reconstr. Surg., 2011, 128(5), 438e-450e.
[http://dx.doi.org/10.1097/PRS.0b013e31822b7352] [PMID: 22030503]
[32]
Wang, J.; Liu, X.; Zhong, Y. Rho/Rho-associated kinase pathway in glaucoma (Review). Int. J. Oncol., 2013, 43(5), 1357-1367.
[http://dx.doi.org/10.3892/ijo.2013.2100] [PMID: 24042317]
[33]
Yamashita, K.; Kotani, Y.; Nakajima, Y.; Shimazawa, M.; Yoshimura, S.; Nakashima, S.; Iwama, T.; Hara, H. Fasudil, a Rho kinase (ROCK) inhibitor, protects against ischemic neuronal damage in vitro and in vivo by acting directly on neurons. Brain Res., 2007, 1154, 215-224.
[http://dx.doi.org/10.1016/j.brainres.2007.04.013] [PMID: 17482584]
[34]
Shaw, P.X.; Sang, A.; Wang, Y.; Ho, D.; Douglas, C.; Dia, L.; Goldberg, J.L. Topical administration of a Rock/Net inhibitor promotes retinal ganglion cell survival and axon regeneration after optic nerve injury. Exp. Eye Res., 2017, 158, 33-42.
[http://dx.doi.org/10.1016/j.exer.2016.07.006] [PMID: 27443501]
[35]
Hove, I.V.; Lefevere, E.; Moons, L. ROCK inhibition as a novel potential strategy for axonal regeneration in optic neuropathies. Neural Regen. Res., 2015, 10(12), 1949-1950.
[http://dx.doi.org/10.4103/1673-5374.172311] [PMID: 26889182]
[36]
Van de Velde, S.; De Groef, L.; Stalmans, I.; Moons, L.; Van Hove, I. Towards axonal regeneration and neuroprotection in glaucoma: Rho kinase inhibitors as promising therapeutics. Prog. Neurobiol., 2015, 131, 105-119.
[http://dx.doi.org/10.1016/j.pneurobio.2015.06.002] [PMID: 26093354]
[37]
Breitenlechner, C.; Gassel, M.; Hidaka, H.; Kinzel, V.; Huber, R.; Engh, R.A.; Bossemeyer, D. Protein kinase A in complex with Rho-kinase inhibitors Y-27632, Fasudil, and H-1152P: structural basis of selectivity. Structure, 2003, 11(12), 1595-1607.
[http://dx.doi.org/10.1016/j.str.2003.11.002] [PMID: 14656443]
[38]
Dong, M.; Yan, B.P.; Liao, J.K.; Lam, Y.Y.; Yip, G.W.K.; Yu, C.M. Rho-kinase inhibition: a novel therapeutic target for the treatment of cardiovascular diseases. Drug Discov. Today, 2010, 15(15-16), 622-629.
[http://dx.doi.org/10.1016/j.drudis.2010.06.011] [PMID: 20601092]
[39]
Guan, R.; Xu, X.; Chen, M.; Hu, H.; Ge, H.; Wen, S.; Zhou, S.; Pi, R. Advances in the studies of roles of Rho/Rho-kinase in diseases and the development of its inhibitors. Eur. J. Med. Chem., 2013, 70, 613-622.
[http://dx.doi.org/10.1016/j.ejmech.2013.10.048] [PMID: 24211637]
[40]
Dhalla, N.S.; Müller, A.L. Protein kinases as drug development targets for heart disease therapy. Pharmaceuticals (Basel), 2010, 3(7), 2111-2145.
[http://dx.doi.org/10.3390/ph3072111] [PMID: 27713345]
[41]
Rikitake, Y.; Kim, H.H.; Huang, Z.; Seto, M.; Yano, K.; Asano, T.; Moskowitz, M.A.; Liao, J.K. Inhibition of Rho kinase (ROCK) leads to increased cerebral blood flow and stroke protection. Stroke, 2005, 36(10), 2251-2257.
[http://dx.doi.org/10.1161/01.STR.0000181077.84981.11] [PMID: 16141422]
[42]
Takami, A.; Iwakubo, M.; Okada, Y.; Kawata, T.; Odai, H.; Takahashi, N.; Shindo, K.; Kimura, K.; Tagami, Y.; Miyake, M.; Fukushima, K.; Inagaki, M.; Amano, M.; Kaibuchi, K.; Iijima, H. Design and synthesis of Rho kinase inhibitors (I). Bioorg. Med. Chem., 2004, 12(9), 2115-2137.
[http://dx.doi.org/10.1016/j.bmc.2004.02.025] [PMID: 15080913]
[43]
Ramachandran, C.; Patil, R.V.; Sharif, N.A.; Srinivas, S.P. Effect of elevated intracellular cAMP levels on actomyosin contraction in bovine trabecular meshwork cells. Invest. Ophthalmol. Vis. Sci., 2011, 52(3), 1474-1485.
[http://dx.doi.org/10.1167/iovs.10-6241] [PMID: 21071747]
[44]
Pan, P.; Shen, M.; Yu, H.; Li, Y.; Li, D.; Hou, T. Advances in the development of Rho-associated protein kinase (ROCK) inhibitors. Drug Discov. Today, 2013, 18(23-24), 1323-1333.
[http://dx.doi.org/10.1016/j.drudis.2013.09.010] [PMID: 24076262]
[45]
Wettschureck, N.; Offermanns, S. Rho/Rho-kinase mediated signaling in physiology and pathophysiology. J. Mol. Med. (Berl.), 2002, 80(10), 629-638.
[http://dx.doi.org/10.1007/s00109-002-0370-2] [PMID: 12395147]
[46]
Riento, K.; Ridley, A.J. Rocks: multifunctional kinases in cell behaviour. Nat. Rev. Mol. Cell Biol., 2003, 4(6), 446-456.
[http://dx.doi.org/10.1038/nrm1128] [PMID: 12778124]
[47]
Shen, M.; Yu, H.; Li, Y.; Li, P.; Pan, P.; Zhou, S.; Zhang, L.; Li, S.; Lee, S.M.; Hou, T. Discovery of Rho-kinase inhibitors by docking-based virtual screening. Mol. Biosyst., 2013, 9(6), 1511-1521.
[http://dx.doi.org/10.1039/c3mb00016h] [PMID: 23549429]
[48]
Julian, L.; Olson, M.F. Rho-associated coiled-coil containing kinases (ROCK): structure, regulation, and functions. Small GTPases, 2014, 5e, 29846.
[http://dx.doi.org/10.4161/sgtp.29846] [PMID: 25010901]
[49]
Kaibuchi, K.; Kuroda, S.; Amano, M. Regulation of the cytoskeleton and cell adhesion by the Rho family GTPases in mammalian cells. Annu. Rev. Biochem., 1999, 68, 459-486.
[http://dx.doi.org/10.1146/annurev.biochem.68.1.459] [PMID: 10872457]
[50]
Dahlmann-Noor, A.H.; Vijay, S.; Limb, G.A.; Khaw, P.T. Strategies for optic nerve rescue and regeneration in glaucoma and other optic neuropathies. Drug Discov. Today, 2010, 15(7-8), 287-299.
[http://dx.doi.org/10.1016/j.drudis.2010.02.007] [PMID: 20197108]
[51]
Trauger, J.W.; Lin, F.F.; Turner, M.S.; Stephens, J.; LoGrasso, P.V. Kinetic mechanism for human Rho-Kinase II (ROCK-II). Biochemistry, 2002, 41(28), 8948-8953.
[http://dx.doi.org/10.1021/bi0258243] [PMID: 12102637]
[52]
Kitaoka, Y.; Kitaoka, Y.; Kumai, T.; Lam, T.T.; Kuribayashi, K.; Isenoumi, K.; Munemasa, Y.; Motoki, M.; Kobayashi, S.; Ueno, S. Involvement of RhoA and possible neuroprotective effect of fasudil, a Rho kinase inhibitor, in NMDA-induced neurotoxicity in the rat retina. Brain Res., 2004, 1018(1), 111-118.
[http://dx.doi.org/10.1016/j.brainres.2004.05.070] [PMID: 15262212]
[53]
Cohen, P. The development and therapeutic potential of protein kinase inhibitors. Curr. Opin. Chem. Biol., 1999, 3(4), 459-465.
[http://dx.doi.org/10.1016/S1367-5931(99)80067-2] [PMID: 10419844]
[54]
Laha, B.; Stafford, B.K.; Huberman, A.D. Regenerating optic pathways from the eye to the brain. Science, 2017, 356(6342), 1031-1034.
[http://dx.doi.org/10.1126/science.aal5060] [PMID: 28596336]
[55]
Kameda, T.; Inoue, T.; Inatani, M.; Fujimoto, T.; Honjo, M.; Kasaoka, N.; Inoue-Mochita, M.; Yoshimura, N.; Tanihara, H. The effect of Rho-associated protein kinase inhibitor on monkey Schlemm’s canal endothelial cells. Invest. Ophthalmol. Vis. Sci., 2012, 53(6), 3092-3103.
[http://dx.doi.org/10.1167/iovs.11-8018] [PMID: 22491412]
[56]
Morrison, J.C.; Cepurna Ying Guo, W.O.; Johnson, E.C. Pathophysiology of human glaucomatous optic nerve damage: insights from rodent models of glaucoma. Exp. Eye Res., 2011, 93(2), 156-164.
[http://dx.doi.org/10.1016/j.exer.2010.08.005] [PMID: 20708000]
[57]
Gupta, N.; Yücel, Y.H. Should we treat the brain in glaucoma? Can. J. Ophthalmol., 2007, 42(3), 409-413.
[http://dx.doi.org/10.3129/i07-051] [PMID: 17508036]
[58]
Mueller, B.K.; Mack, H.; Teusch, N. Rho kinase, a promising drug target for neurological disorders. Nat. Rev. Drug Discov., 2005, 4(5), 387-398.
[http://dx.doi.org/10.1038/nrd1719] [PMID: 15864268]
[59]
Sato, M.; Tani, E.; Fujikawa, H.; Kaibuchi, K. Involvement of Rho-kinase-mediated phosphorylation of myosin light chain in enhancement of cerebral vasospasm. Circ. Res., 2000, 87(3), 195-200.
[http://dx.doi.org/10.1161/01.RES.87.3.195] [PMID: 10926869]
[60]
Okumura, N.; Okazaki, Y.; Inoue, R.; Kakutani, K.; Nakano, S.; Kinoshita, S.; Koizumi, N. Effect of the Rho-associated kinase inhibitor eye drop (ripasudil) on corneal endothelial wound healing. Invest. Ophthalmol. Vis. Sci., 2016, 57(3), 1284-1292.
[http://dx.doi.org/10.1167/iovs.15-18586] [PMID: 26998714]
[61]
Ohta, Y.; Takaseki, S.; Yoshitomi, T. Effects of ripasudil hydrochloride hydrate (K-115), a Rho-kinase inhibitor, on ocular blood flow and ciliary artery smooth muscle contraction in rabbits. Jpn. J. Ophthalmol., 2017, 61(5), 423-432.
[http://dx.doi.org/10.1007/s10384-017-0524-y] [PMID: 28653193]
[62]
Shahidullah, M.; Al-Malki, W.H.; Delamere, N.A. Mechanism of aqueous humor secretion, its regulation and relevance to glaucoma; Glaucoma-Basic and Clinical Concepts 1st ed, 2011, pp. 3-32.
[http://dx.doi.org/10.5772/26559]
[63]
Carreon, T.; van der Merwe, E.; Fellman, R.L.; Johnstone, M.; Bhattacharya, S.K. Aqueous outflow - A continuum from trabecular meshwork to episcleral veins. Prog. Retin. Eye Res., 2017, 57, 108-133.
[http://dx.doi.org/10.1016/j.preteyeres.2016.12.004] [PMID: 28028002]
[64]
Roy Chowdhury, U.; Hann, C.R.; Stamer, W.D.; Fautsch, M.P. Aqueous humor outflow: dynamics and disease. Invest. Ophthalmol. Vis. Sci., 2015, 56(5), 2993-3003.
[http://dx.doi.org/10.1167/iovs.15-16744] [PMID: 26024085]
[65]
Johnson, M.; McLaren, J.W.; Overby, D.R. Unconventional aqueous humor outflow: A review. Exp. Eye Res., 2017, 158, 94-111.
[http://dx.doi.org/10.1016/j.exer.2016.01.017] [PMID: 26850315]
[66]
Goldhagen, B.; Proia, A.D.; Epstein, D.L.; Rao, P.V. Elevated levels of RhoA in the optic nerve head of human eyes with glaucoma. J. Glaucoma, 2012, 21(8), 530-538.
[http://dx.doi.org/10.1097/IJG.0b013e318241b83c] [PMID: 22495072]
[67]
Ramachandran, C.; Patil, R.V.; Combrink, K.; Sharif, N.A.; Srinivas, S.P. Rho-Rho kinase pathway in the actomyosin contraction and cell-matrix adhesion in immortalized human trabecular meshwork cells. Mol. Vis., 2011, 17, 1877-1890.
[PMID: 21850162]
[68]
Tian, B.; Geiger, B.; Epstein, D.L.; Kaufman, P.L. Cytoskeletal involvement in the regulation of aqueous humor outflow. Invest. Ophthalmol. Vis. Sci., 2000, 41(3), 619-623.
[PMID: 10711672]
[69]
Acott, T.S.; Kelley, M.J. Extracellular matrix in the trabecular meshwork. Exp. Eye Res., 2008, 86(4), 543-561.
[http://dx.doi.org/10.1016/j.exer.2008.01.013] [PMID: 18313051]
[70]
Tian, B.; Gabelt, B.T.; Geiger, B.; Kaufman, P.L. The role of the actomyosin system in regulating trabecular fluid outflow. Exp. Eye Res., 2009, 88(4), 713-717.
[http://dx.doi.org/10.1016/j.exer.2008.08.008] [PMID: 18793636]
[71]
Lütjen-Drecoll, E. Functional morphology of the trabecular meshwork in primate eyes. Prog. Retin. Eye Res., 1999, 18(1), 91-119.
[http://dx.doi.org/10.1016/S1350-9462(98)00011-1] [PMID: 9920500]
[72]
Pattabiraman, P.P.; Rao, P.V. Mechanistic basis of Rho GTPase-induced extracellular matrix synthesis in trabecular meshwork cells. Am. J. Physiol. Cell Physiol., 2010, 298(3), C749-C763.
[http://dx.doi.org/10.1152/ajpcell.00317.2009] [PMID: 19940066]
[73]
Mandell, K.J.; Kudelka, M.R.; Wirostko, B. Rho kinase inhibitors for treatment of glaucoma. Expert Rev. Ophthalmol., 2011, 6(6), 611-622.
[http://dx.doi.org/10.1586/eop.11.65] [PMID: 30613208]
[74]
Zhang, M.; Maddala, R.; Rao, P.V. Novel molecular insights into RhoA GTPase-induced resistance to aqueous humor outflow through the trabecular meshwork. Am. J. Physiol. Cell Physiol., 2008, 295(5), C1057-C1070.
[http://dx.doi.org/10.1152/ajpcell.00481.2007] [PMID: 18799648]
[75]
Honjo, M.; Tanihara, H.; Inatani, M.; Kido, N.; Sawamura, T.; Yue, B.Y.; Narumiya, S.; Honda, Y. Effects of rho-associated protein kinase inhibitor Y-27632 on intraocular pressure and outflow facility. Invest. Ophthalmol. Vis. Sci., 2001, 42(1), 137-144.
[PMID: 11133858]
[76]
Koga, T.; Koga, T.; Awai, M.; Tsutsui, J.; Yue, B.Y.; Tanihara, H. Rho-associated protein kinase inhibitor, Y-27632, induces alterations in adhesion, contraction and motility in cultured human trabecular meshwork cells. Exp. Eye Res., 2006, 82(3), 362-370.
[http://dx.doi.org/10.1016/j.exer.2005.07.006] [PMID: 16125171]
[77]
Honjo, M.; Inatani, M.; Kido, N.; Sawamura, T.; Yue, B.Y.; Honda, Y.; Tanihara, H. Effects of protein kinase inhibitor, HA1077, on intraocular pressure and outflow facility in rabbit eyes. Arch. Ophthalmol., 2001, 119(8), 1171-1178.
[http://dx.doi.org/10.1001/archopht.119.8.1171] [PMID: 11483085]
[78]
Tokushige, H.; Inatani, M.; Nemoto, S.; Sakaki, H.; Katayama, K.; Uehata, M.; Tanihara, H. Effects of topical administration of y-39983, a selective rho-associated protein kinase inhibitor, on ocular tissues in rabbits and monkeys. Invest. Ophthalmol. Vis. Sci., 2007, 48(7), 3216-3222.
[http://dx.doi.org/10.1167/iovs.05-1617] [PMID: 17591891]
[79]
Williams, R.D.; Novack, G.D.; van Haarlem, T.; Kopczynski, C. AR-12286 Phase 2A Study Group. Ocular hypotensive effect of the Rho kinase inhibitor AR-12286 in patients with glaucoma and ocular hypertension. Am. J. Ophthalmol., 2011, 152(5), 834-41.e1.
[http://dx.doi.org/10.1016/j.ajo.2011.04.012] [PMID: 21794845]
[80]
Yu, M.; Chen, X.; Wang, N.; Cai, S.; Li, N.; Qiu, J.; Brandt, C.R.; Kaufman, P.L.; Liu, X. H-1152 effects on intraocular pressure and trabecular meshwork morphology of rat eyes. J. Ocul. Pharmacol. Ther., 2008, 24(4), 373-379.
[http://dx.doi.org/10.1089/jop.2008.0029] [PMID: 18665808]
[81]
Tanihara, H.; Inoue, T.; Yamamoto, T.; Kuwayama, Y.; Abe, H.; Araie, M. K-115 Clinical Study Group. Phase 2 randomized clinical study of a Rho kinase inhibitor, K-115, in primary open-angle glaucoma and ocular hypertension. Am. J. Ophthalmol., 2013, 156(4), 731-736.
[http://dx.doi.org/10.1016/j.ajo.2013.05.016] [PMID: 23831221]
[82]
Honjo, M.; Tanihara, H.; Kameda, T.; Kawaji, T.; Yoshimura, N.; Araie, M. Potential role of Rho-associated protein kinase inhibitor Y-27632 in glaucoma filtration surgery. Invest. Ophthalmol. Vis. Sci., 2007, 48(12), 5549-5557.
[http://dx.doi.org/10.1167/iovs.07-0878] [PMID: 18055804]
[83]
Van de. V. S.; Bergen, T. V.; Vandewalle, E.; Moons, L.; Stalmans, I. Modulation of Wound Healing in Glaucoma Surgery. Prog. Brain Res., 2015, 21, 530-538.
[84]
Khaw, P.T.; Chang, L.; Wong, T.T.; Mead, A.; Daniels, J.T.; Cordeiro, M.F. Modulation of wound healing after glaucoma surgery. Curr. Opin. Ophthalmol., 2001, 12(2), 143-148.
[http://dx.doi.org/10.1097/00055735-200104000-00011] [PMID: 11224722]
[85]
Gressel, M.G.; Parrish, R.K., II; Folberg, R. 5-fluorouracil and glaucoma filtering surgery: I. An animal model. Ophthalmology, 1984, 91(4), 378-383.
[http://dx.doi.org/10.1016/S0161-6420(84)34277-4] [PMID: 6717922]
[86]
Wong, T.T.; Mead, A.L.; Khaw, P.T. Prolonged antiscarring effects of ilomastat and MMC after experimental glaucoma filtration surgery. Invest. Ophthalmol. Vis. Sci., 2005, 46(6), 2018-2022.
[http://dx.doi.org/10.1167/iovs.04-0820] [PMID: 15914618]
[87]
Humphrey, J.D.; Dufresne, E.R.; Schwartz, M.A. Mechanotransduction and extracellular matrix homeostasis. Nat. Rev. Mol. Cell Biol., 2014, 15(12), 802-812.
[http://dx.doi.org/10.1038/nrm3896] [PMID: 25355505]
[88]
Rocha-Sousa, A.; Rodrigues-Araújo, J.; Gouveia, P.; Barbosa-Breda, J.; Azevedo-Pinto, S.; Pereira-Silva, P.; Leite-Moreira, A. New therapeutic targets for intraocular pressure lowering. ISRN Ophthalmol., 2013, 2013261386
[http://dx.doi.org/10.1155/2013/261386] [PMID: 24558600]
[89]
Tura, A.; Grisanti, S.; Petermeier, K.; Henke-Fahle, S. The Rho-kinase inhibitor H-1152P suppresses the wound-healing activities of human Tenon’s capsule fibroblasts in vitro. Invest. Ophthalmol. Vis. Sci., 2007, 48(5), 2152-2161.
[http://dx.doi.org/10.1167/iovs.06-1271] [PMID: 17460274]
[90]
Whitlock, N.A.; Harrison, B.; Mixon, T.; Yu, X.Q.; Wilson, A.; Gerhardt, B.; Eberhart, D.E.; Abuin, A.; Rice, D.S. Decreased intraocular pressure in mice following either pharmacological or genetic inhibition of ROCK. J. Ocul. Pharmacol. Ther., 2009, 25(3), 187-194.
[http://dx.doi.org/10.1089/jop.2008.0142] [PMID: 19456252]
[91]
Waki, M.; Yoshida, Y.; Oka, T.; Azuma, M. Reduction of intraocular pressure by topical administration of an inhibitor of the Rho-associated protein kinase. Curr. Eye Res., 2001, 22(6), 470-474.
[http://dx.doi.org/10.1076/ceyr.22.6.470.5489] [PMID: 11584347]
[92]
Tanihara, H.; Inatani, M.; Honjo, M.; Tokushige, H.; Azuma, J.; Araie, M. Intraocular pressure-lowering effects and safety of topical administration of a selective ROCK inhibitor, SNJ-1656, in healthy volunteers. Arch. Ophthalmol., 2008, 126(3), 309-315.
[http://dx.doi.org/10.1001/archophthalmol.2007.76] [PMID: 18332309]
[93]
Pattabiraman, P.P.; Rinkoski, T.; Poeschla, E.; Proia, A.; Challa, P.; Rao, P.V.; Rho, A. RhoA GTPase-induced ocular hypertension in a rodent model is associated with increased fibrogenic activity in the trabecular meshwork. Am. J. Pathol., 2015, 185(2), 496-512.
[http://dx.doi.org/10.1016/j.ajpath.2014.10.023] [PMID: 25499974]
[94]
Siegner, S.W.; Netland, P.A. Optic disc hemorrhages and progression of glaucoma. Ophthalmology, 1996, 103(7), 1014-1024.
[http://dx.doi.org/10.1016/S0161-6420(96)30572-1] [PMID: 8684789]
[95]
Krupin, T.; Liebmann, J.M.; Greenfield, D.S.; Rosenberg, L.F.; Ritch, R.; Yang, J.W. Low-Pressure Glaucoma Study Group. The Low-pressure Glaucoma Treatment Study (LoGTS) study design and baseline characteristics of enrolled patients. Ophthalmology, 2005, 112(3), 376-385.
[http://dx.doi.org/10.1016/j.ophtha.2004.10.034] [PMID: 15745762]
[96]
Okamura, N.; Saito, M.; Mori, A.; Sakamoto, K.; Kametaka, S.; Nakahara, T.; Ishii, K. Vasodilator effects of fasudil, a Rho-kinase inhibitor, on retinal arterioles in stroke-prone spontaneously hypertensive rats. J. Ocul. Pharmacol. Ther., 2007, 23(3), 207-212.
[http://dx.doi.org/10.1089/jop.2006.128] [PMID: 17593003]
[97]
Watabe, H.; Abe, S.; Yoshitomi, T. Effects of Rho-associated protein kinase inhibitors Y-27632 and Y-39983 on isolated rabbit ciliary arteries. Jpn. J. Ophthalmol., 2011, 55(4), 411-417.
[http://dx.doi.org/10.1007/s10384-011-0048-9] [PMID: 21667088]
[98]
Sugiyama, T.; Shibata, M.; Kajiura, S.; Okuno, T.; Tonari, M.; Oku, H.; Ikeda, T. Effects of fasudil, a Rho-associated protein kinase inhibitor, on optic nerve head blood flow in rabbits. Invest. Ophthalmol. Vis. Sci., 2011, 52(1), 64-69.
[http://dx.doi.org/10.1167/iovs.10-5265] [PMID: 20720232]
[99]
Nakabayashi, S.; Kawai, M.; Yoshioka, T.; Song, Y.S.; Tani, T.; Yoshida, A.; Nagaoka, T. Effect of intravitreal Rho kinase inhibitor ripasudil (K-115) on feline retinal microcirculation. Exp. Eye Res., 2015, 139, 132-135.
[http://dx.doi.org/10.1016/j.exer.2015.07.008] [PMID: 26197413]
[100]
Alexandrescu, C.; Dascalu, A.M.; Mitulescu, C.; Panca, A.; Pascu, R.; Ciuluvica, R.; Potop, V.; Voinea, L.M. Evidence-based pathophysiology of glaucoma. Maedica (Buchar.), 2010, 5(3), 207-213.
[PMID: 21977154]
[101]
Saccà, S.C.; Izzotti, A. Oxidative stress and glaucoma: injury in the anterior segment of the eye. Prog. Brain Res., 2008, 173, 385-407.
[http://dx.doi.org/10.1016/S0079-6123(08)01127-8] [PMID: 18929123]
[102]
Oshida, E.; Matsumoto, Y.; Arai, K. Free radicals in the aqueous humor of patients with glaucoma. Clin. Ophthalmol., 2010, 4, 653-660.
[http://dx.doi.org/10.2147/OPTH.S10922] [PMID: 20689778]
[103]
Izzotti, A.; Bagnis, A.; Saccà, S.C. The role of oxidative stress in glaucoma. Mutat. Res., 2006, 612(2), 105-114.
[http://dx.doi.org/10.1016/j.mrrev.2005.11.001] [PMID: 16413223]
[104]
Tokushige, H.; Waki, M.; Takayama, Y.; Tanihara, H. 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. Curr. Eye Res., 2011, 36(10), 964-970.
[http://dx.doi.org/10.3109/02713683.2011.599106] [PMID: 21950703]
[105]
Sagawa, H.; Terasaki, H.; Nakamura, M.; Ichikawa, M.; Yata, T.; Tokita, Y.; Watanabe, M. A novel ROCK inhibitor, Y-39983, promotes regeneration of crushed axons of retinal ganglion cells into the optic nerve of adult cats. Exp. Neurol., 2007, 205(1), 230-240.
[http://dx.doi.org/10.1016/j.expneurol.2007.02.002] [PMID: 17359977]
[106]
Bertrand, J.; Winton, M.J.; Rodriguez-Hernandez, N.; Campenot, R.B.; McKerracher, L. Application of Rho antagonist to neuronal cell bodies promotes neurite growth in compartmented cultures and regeneration of retinal ganglion cell axons in the optic nerve of adult rats. J. Neurosci., 2005, 25(5), 1113-1121.
[http://dx.doi.org/10.1523/JNEUROSCI.3931-04.2005] [PMID: 15689547]
[107]
Yamamoto, K.; Maruyama, K.; Himori, N.; Omodaka, K.; Yokoyama, Y.; Shiga, Y.; Morin, R.; Nakazawa, T. The novel Rho kinase (ROCK) inhibitor K-115: a new candidate drug for neuroprotective treatment in glaucoma. Invest. Ophthalmol. Vis. Sci., 2014, 55(11), 7126-7136.
[http://dx.doi.org/10.1167/iovs.13-13842] [PMID: 25277230]
[108]
Iwakubo, M.; Takami, A.; Okada, Y.; Kawata, T.; Tagami, Y.; Sato, M.; Sugiyama, T.; Fukushima, K.; Taya, S.; Amano, M.; Kaibuchi, K.; Iijima, H. Design and synthesis of rho kinase inhibitors (III). Bioorg. Med. Chem., 2007, 15(2), 1022-1033.
[http://dx.doi.org/10.1016/j.bmc.2006.10.028] [PMID: 17084087]
[109]
Challa, P.; Arnold, J.J. Rho-kinase inhibitors offer a new approach in the treatment of glaucoma. Expert Opin. Investig. Drugs, 2014, 23(1), 81-95.
[http://dx.doi.org/10.1517/13543784.2013.840288] [PMID: 24094075]
[110]
Shah, S.; Savjani, J. A review on ROCK-II inhibitors: From molecular modelling to synthesis. Bioorg. Med. Chem. Lett., 2016, 26(10), 2383-2391.
[http://dx.doi.org/10.1016/j.bmcl.2016.03.113] [PMID: 27080184]
[111]
Sessions, E.H.; Smolinski, M.; Wang, B.; Frackowiak, B.; Chowdhury, S.; Yin, Y.; Chen, Y.T.; Ruiz, C.; Lin, L.; Pocas, J.; Schröter, T.; Cameron, M.D.; LoGrasso, P.; Feng, Y.; Bannister, T.D. The development of benzimidazoles as selective rho kinase inhibitors. Bioorg. Med. Chem. Lett., 2010, 20(6), 1939-1943.
[http://dx.doi.org/10.1016/j.bmcl.2010.01.124] [PMID: 20167489]
[112]
Feng, Y.; LoGrasso, P.V.; Defert, O.; Li, R. Rho Kinase (ROCK) inhibitors and their therapeutic potential. J. Med. Chem., 2016, 59(6), 2269-2300.
[http://dx.doi.org/10.1021/acs.jmedchem.5b00683] [PMID: 26486225]
[113]
Roser, A.E.; Tönges, L.; Lingor, P. Modulation of microglial activity by Rho-kinase (ROCK) inhibition as therapeutic strategy in parkinson’s disease and amyotrophic lateral sclerosis. Front. Aging Neurosci., 2017, 9, 94.
[http://dx.doi.org/10.3389/fnagi.2017.00094] [PMID: 28420986]
[114]
Kubo, T.; Yamaguchi, A.; Iwata, N.; Yamashita, T. The therapeutic effects of Rho-ROCK inhibitors on CNS disorders. Ther. Clin. Risk Manag., 2008, 4(3), 605-615.
[http://dx.doi.org/10.2147/TCRM.S2907] [PMID: 18827856]
[115]
Wang, S.K.; Chang, R.T. An emerging treatment option for glaucoma: Rho kinase inhibitors. Clin. Ophthalmol., 2014, 8, 883-890.
[http://dx.doi.org/10.2147/OPTH.S41000] [PMID: 24872673]
[116]
Shen, M.; Tian, S.; Pan, P.; Sun, H.; Li, D.; Li, Y.; Zhou, H.; Li, C.; Lee, S.M.; Hou, T. Discovery of novel ROCK1 inhibitors via integrated virtual screening strategy and bioassays. Sci. Rep., 2015, 5, 16749.
[http://dx.doi.org/10.1038/srep16749] [PMID: 26568382]
[117]
Chico, L.K.; Van Eldik, L.J.; Watterson, D.M. Targeting protein kinases in central nervous system disorders. Nat. Rev. Drug Discov., 2009, 8(11), 892-909.
[http://dx.doi.org/10.1038/nrd2999] [PMID: 19876042]
[118]
Ichikawa, M.; Yoshida, J.; Saito, K.; Sagawa, H.; Tokita, Y.; Watanabe, M. Differential effects of two ROCK inhibitors, Fasudil and Y-27632, on optic nerve regeneration in adult cats. Brain Res., 2008, 1201, 23-33.
[http://dx.doi.org/10.1016/j.brainres.2008.01.063] [PMID: 18313036]
[119]
Iwakubo, M.; Okada, Y. Isoquinoline Derivatives Having Kinase Inhibitory Activity and Drugs Containing the Same. WO Patent 2004024717, 2004.
[120]
Sturdivant, J.M.; Royalty, S.M.; Lin, C.W.; Moore, L.A.; Yingling, J.D.; Laethem, C.L.; Sherman, B.; Heintzelman, G.R.; Kopczynski, C.C.; deLong, M.A. Discovery of the ROCK inhibitor netarsudil for the treatment of open-angle glaucoma. Bioorg. Med. Chem. Lett., 2016, 26(10), 2475-2480.
[http://dx.doi.org/10.1016/j.bmcl.2016.03.104] [PMID: 27072905]
[121]
Garnock-Jones, K.P. Ripasudil: first global approval. Drugs, 2014, 74(18), 2211-2215.
[http://dx.doi.org/10.1007/s40265-014-0333-2] [PMID: 25414122]
[122]
Koch, J.C.; Tatenhorst, L.; Roser, A.E.; Saal, K.A.; Tönges, L.; Lingor, P. ROCK inhibition in models of neurodegeneration and its potential for clinical translation. Pharmacol. Ther., 2018, 189, 1-21.
[http://dx.doi.org/10.1016/j.pharmthera.2018.03.008] [PMID: 29621594]
[123]
Logé, C.; Siomboing, X.; Wallez, V.; Scalbert, E.; Bennejean, C.; Cario-Tourmaniantz, C.; Loirand, G.; Gressier, B.; Pacaud, P.; Luyckx, M. Synthesis and pharmacological study of Rho-kinase inhibitors: pharmacomodulations on the lead compound Fasudil. J. Enzyme Inhib. Med. Chem., 2003, 18(2), 127-138.
[http://dx.doi.org/10.1080/1475636031000093561] [PMID: 12943196]
[124]
Aerie Pharmaceuticals; Double-Masked Study of Netarsudil (AR-13324) Ophthalmic Solution in Subjects with Glaucoma or Ocular Hypertension., Available at:. https://clinicaltrials. gov/ct2/ show/NCT02558374 [Accessed: Dec 3, 2016].
[125]
Ishizaki, T.; Uehata, M.; Tamechika, I.; Keel, J.; Nonomura, K.; Maekawa, M.; Narumiya, S. Pharmacological properties of Y-27632, a specific inhibitor of rho-associated kinases. Mol. Pharmacol., 2000, 57(5), 976-983.
[PMID: 10779382]
[126]
Gingras, K.; Avedissian, H.; Thouin, E.; Boulanger, V.; Essagian, C.; McKerracher, L.; Lubell, W.D. Synthesis and evaluation of 4-(1-aminoalkyl)-N-(4-pyridyl)cyclohexanecarboxamides as Rho kinase inhibitors and neurite outgrowth promoters. Bioorg. Med. Chem. Lett., 2004, 14(19), 4931-4934.
[http://dx.doi.org/10.1016/j.bmcl.2004.07.025] [PMID: 15341954]
[127]
McKerracher, L.T.E.; Lubell, W.D. 1, 4-Substituted Cyclohexane Derivatives. WO Patent 2004022541, 2004.
[128]
Logé, C.; Wallez, V.; Scalbert, E.; Cario-Tourmaniantz, C.; Loirand, G.; Pacaud, P.; Lesieur, D. Rho-kinase inhibitors: pharmacomodulations on the lead compound Y-32885. J. Enzyme Inhib. Med. Chem., 2002, 17(6), 381-390.
[http://dx.doi.org/10.1080/1475636021000005659] [PMID: 12683673]
[129]
Kalyaanamoorthy, S.; Chen, Y.P. Structure-based drug design to augment hit discovery. Drug Discov. Today, 2011, 16(17-18), 831-839.
[http://dx.doi.org/10.1016/j.drudis.2011.07.006] [PMID: 21810482]
[130]
Goodman, K.B.; Cui, H.; Dowdell, S.E.; Gaitanopoulos, D.E.; Ivy, R.L.; Sehon, C.A.; Stavenger, R.A.; Wang, G.Z.; Viet, A.Q.; Xu, W.; Ye, G.; Semus, S.F.; Evans, C.; Fries, H.E.; Jolivette, L.J.; Kirkpatrick, R.B.; Dul, E.; Khandekar, S.S.; Yi, T.; Jung, D.K.; Wright, L.L.; Smith, G.K.; Behm, D.J.; Bentley, R.; Doe, C.P.; Hu, E.; Lee, D. Development of dihydropyridone indazole amides as selective Rho-kinase inhibitors. J. Med. Chem., 2007, 50(1), 6-9.
[http://dx.doi.org/10.1021/jm0609014] [PMID: 17201405]
[131]
Oh, K.S.; Oh, B.K.; Park, C.H.; Seo, H.W.; Kang, N.S.; Lee, J.H.; Lee, J.S.; Ho Lee, B. Cardiovascular effects of a novel selective Rho kinase inhibitor, 2-(1H-indazole-5-yl)amino-4-methoxy-6-piperazino triazine (DW1865). Eur. J. Pharmacol., 2013, 702(1-3), 218-226.
[http://dx.doi.org/10.1016/j.ejphar.2013.01.027] [PMID: 23376156]
[132]
Feng, Y.; Cameron, M.D.; Frackowiak, B.; Griffin, E.; Lin, L.; Ruiz, C.; Schröter, T.; LoGrasso, P. Structure-activity relationships, and drug metabolism and pharmacokinetic properties for indazole piperazine and indazole piperidine inhibitors of ROCK-II. Bioorg. Med. Chem. Lett., 2007, 17(8), 2355-2360.
[http://dx.doi.org/10.1016/j.bmcl.2006.12.043] [PMID: 17368019]
[133]
Iwakubo, M.; Takami, A.; Okada, Y.; Kawata, T.; Tagami, Y.; Ohashi, H.; Sato, M.; Sugiyama, T.; Fukushima, K.; Iijima, H. Design and synthesis of Rho kinase inhibitors (II). Bioorg. Med. Chem., 2007, 15(1), 350-364.
[http://dx.doi.org/10.1016/j.bmc.2006.09.052] [PMID: 17046269]
[134]
Feng, Y.; Yin, Y.; Weiser, A.; Griffin, E.; Cameron, M.D.; Lin, L.; Ruiz, C.; Schürer, S.C.; Inoue, T.; Rao, P.V.; Schröter, T.; Lograsso, P. Discovery of substituted 4-(pyrazol-4-yl)-phenylbenzodioxane-2-carboxamides as potent and highly selective Rho kinase (ROCK-II) inhibitors. J. Med. Chem., 2008, 51(21), 6642-6645.
[http://dx.doi.org/10.1021/jm800986w] [PMID: 18834107]
[135]
Chen, Y.T.; Bannister, T.D.; Weiser, A.; Griffin, E.; Lin, L.; Ruiz, C.; Cameron, M.D.; Schürer, S.; Duckett, D.; Schröter, T.; LoGrasso, P.; Feng, Y. Chroman-3-amides as potent Rho kinase inhibitors. Bioorg. Med. Chem. Lett., 2008, 18(24), 6406-6409.
[http://dx.doi.org/10.1016/j.bmcl.2008.10.080] [PMID: 18990570]
[136]
Sessions, E.H.; Yin, Y.; Bannister, T.D.; Weiser, A.; Griffin, E.; Pocas, J.; Cameron, M.D.; Ruiz, C.; Lin, L.; Schürer, S.C.; Schröter, T.; LoGrasso, P.; Feng, Y. Benzimidazole- and benzoxazole-based inhibitors of Rho kinase. Bioorg. Med. Chem. Lett., 2008, 18(24), 6390-6393.
[http://dx.doi.org/10.1016/j.bmcl.2008.10.095] [PMID: 18996009]
[137]
Singla, P.; Luxami, V.; Paul, K. Benzimidazole-biologically attractive scaffold for protein kinase inhibitors. RSC Advances, 2014, 4, 12422-12440.
[http://dx.doi.org/10.1039/c3ra46304d]
[138]
Burger, A. Isosterism and bioisosterism in drug design. Prog. Drug Res., 1991, 37, 287-371.
[http://dx.doi.org/10.1007/978-3-0348-7139-6_7] [PMID: 1763185]
[139]
Olesen, P.H. The use of bioisosteric groups in lead optimization. Curr. Opin. Drug Discov. Devel., 2001, 4(4), 471-478.
[PMID: 11727312]
[140]
Yin, Y.; Lin, L.; Ruiz, C.; Cameron, M.D.; Pocas, J.; Grant, W.; Schröter, T.; Chen, W.; Duckett, D.; Schürer, S.; Lograsso, P.; Feng, Y. Benzothiazoles as Rho-associated kinase (ROCK-II) inhibitors. Bioorg. Med. Chem. Lett., 2009, 19(23), 6686-6690.
[http://dx.doi.org/10.1016/j.bmcl.2009.09.115] [PMID: 19837589]
[141]
Kiyoi, T.; York, M.; Francis, S.; Edwards, D.; Walker, G.; Houghton, A.K.; Cottney, J.E.; Baker, J.; Adam, J.M. Design, synthesis, and structure-activity relationship study of conformationally constrained analogs of indole-3-carboxamides as novel CB1 cannabinoid receptor agonists. Bioorg. Med. Chem. Lett., 2010, 20(16), 4918-4921.
[http://dx.doi.org/10.1016/j.bmcl.2010.06.067] [PMID: 20634067]
[142]
Chowdhury, S.; Sessions, E.H.; Pocas, J.R.; Grant, W.; Schröter, T.; Lin, L.; Ruiz, C.; Cameron, M.D.; Schürer, S.; LoGrasso, P.; Bannister, T.D.; Feng, Y. Discovery and optimization of indoles and 7-azaindoles as Rho kinase (ROCK) inhibitors (part-I). Bioorg. Med. Chem. Lett., 2011, 21(23), 7107-7112.
[http://dx.doi.org/10.1016/j.bmcl.2011.09.083] [PMID: 22004718]
[143]
Sessions, E.H.; Chowdhury, S.; Yin, Y.; Pocas, J.R.; Grant, W.; Schröter, T.; Lin, L.; Ruiz, C.; Cameron, M.D.; LoGrasso, P.; Bannister, T.D.; Feng, Y. Discovery and optimization of indole and 7-azaindoles as Rho kinase (ROCK) inhibitors (part-II). Bioorg. Med. Chem. Lett., 2011, 21(23), 7113-7118.
[http://dx.doi.org/10.1016/j.bmcl.2011.09.084] [PMID: 22018789]
[144]
Fang, X.; Chen, Y.T.; Sessions, E.H.; Chowdhury, S.; Vojkovsky, T.; Yin, Y.; Pocas, J.R.; Grant, W.; Schröter, T.; Lin, L.; Ruiz, C.; Cameron, M.D.; LoGrasso, P.; Bannister, T.D.; Feng, Y. Synthesis and biological evaluation of 4-quinazolinones as Rho kinase inhibitors. Bioorg. Med. Chem. Lett., 2011, 21(6), 1844-1848.
[http://dx.doi.org/10.1016/j.bmcl.2011.01.039] [PMID: 21349713]
[145]
Chowdhury, S.; Chen, Y.T.; Fang, X.; Grant, W.; Pocas, J.; Cameron, M.D.; Ruiz, C.; Lin, L.; Park, H.; Schröter, T.; Bannister, T.D.; Lograsso, P.V.; Feng, Y. Amino acid derived quinazolines as Rock/PKA inhibitors. Bioorg. Med. Chem. Lett., 2013, 23(6), 1592-1599.
[http://dx.doi.org/10.1016/j.bmcl.2013.01.109] [PMID: 23416002]
[146]
Henderson, A.J.; Hadden, M.; Guo, C.; Douglas, N.; Decornez, H.; Hellberg, M.R.; Rusinko, A.; McLaughlin, M.; Sharif, N.; Drace, C.; Patil, R. 2,3-Diaminopyrazines as Rho kinase inhibitors. Bioorg. Med. Chem. Lett., 2010, 20(3), 1137-1140.
[http://dx.doi.org/10.1016/j.bmcl.2009.12.012] [PMID: 20022494]
[147]
Davis, R.L.; Kahraman, M.; Prins, T.J.; Beaver, Y.; Cook, T.G.; Cramp, J.; Cayanan, C.S.; Gardiner, E.M.; McLaughlin, M.A.; Clark, A.F.; Hellberg, M.R.; Shiau, A.K.; Noble, S.A.; Borchardt, A.J. Benzothiophene containing Rho kinase inhibitors: Efficacy in an animal model of glaucoma. Bioorg. Med. Chem. Lett., 2010, 20(11), 3361-3366.
[http://dx.doi.org/10.1016/j.bmcl.2010.04.020] [PMID: 20434334]
[148]
Fang, X.; Yin, Y.; Chen, Y.T.; Yao, L.; Wang, B.; Cameron, M.D.; Lin, L.; Khan, S.; Ruiz, C.; Schröter, T.; Grant, W.; Weiser, A.; Pocas, J.; Pachori, A.; Schürer, S.; Lograsso, P.; Feng, Y. Tetrahydroisoquinoline derivatives as highly selective and potent Rho kinase inhibitors. J. Med. Chem., 2010, 53(15), 5727-5737.
[http://dx.doi.org/10.1021/jm100579r] [PMID: 20684608]
[149]
Green, J.; Cao, J.; Bandarage, U.K.; Gao, H.; Court, J.; Marhefka, C.; Jacobs, M.; Taslimi, P.; Newsome, D.; Nakayama, T.; Shah, S.; Rodems, S. Design, synthesis, and structure-activity relationships of pyridine-based Rho kinase (ROCK) inhibitors. J. Med. Chem., 2015, 58(12), 5028-5037.
[http://dx.doi.org/10.1021/acs.jmedchem.5b00424] [PMID: 26039570]
[150]
Yin, Y.; Cameron, M.D.; Lin, L.; Khan, S.; Schröter, T.; Grant, W.; Pocas, J.; Chen, Y.T.; Schürer, S.; Pachori, A.; LoGrasso, P.; Feng, Y. Discovery of potent and selective urea-based ROCK inhibitors and their effects on intraocular pressure in rats. ACS Med. Chem. Lett., 2010, 1(4), 175-179.
[http://dx.doi.org/10.1021/ml1000382] [PMID: 24900192]
[151]
Yin, Y.; Lin, L.; Ruiz, C.; Khan, S.; Cameron, M.D.; Grant, W.; Pocas, J.; Eid, N.; Park, H.; Schröter, T.; Lograsso, P.V.; Feng, Y. Synthesis and biological evaluation of urea derivatives as highly potent and selective rho kinase inhibitors. J. Med. Chem., 2013, 56(9), 3568-3581.
[http://dx.doi.org/10.1021/jm400062r] [PMID: 23570561]
[152]
Vohra, V.; Chawla, H.; Gupta, M. ROCK Inhibitors: Future of anti-glaucoma medication. Ophthalmol. Res. Int. J., 2014, 2, 361-367.
[http://dx.doi.org/10.9734/OR/2014/10573]
[153]
Inoue, T.; Tanihara, H. Ripasudil hydrochloride hydrate: targeting Rho kinase in the treatment of glaucoma. Expert Opin. Pharmacother., 2017, 18(15), 1669-1673.
[http://dx.doi.org/10.1080/14656566.2017.1378344] [PMID: 28893104]
[154]
Van de Velde, S.; Van Bergen, T.; Sijnave, D.; Hollanders, K.; Castermans, K.; Defert, O.; Leysen, D.; Vandewalle, E.; Moons, L.; Stalmans, I. AMA0076, a novel, locally acting Rho kinase inhibitor, potently lowers intraocular pressure in New Zealand white rabbits with minimal hyperemia. Invest. Ophthalmol. Vis. Sci., 2014, 55(2), 1006-1016.
[http://dx.doi.org/10.1167/iovs.13-13157] [PMID: 24474276]
[155]
Abbhi, V.; Piplani, P. Rho Kinase inhibitors and novel ocular drug delivery systems- a revolutionary step towards the treatment of glaucoma. Curr. Drug Deliv., 2016, 13(6), 818-829.
[http://dx.doi.org/10.2174/09298665113209990057] [PMID: 23855668]
[156]
Amakem Begins Phase II Trial for Locally-Acting ROCK Inhibitor AMA0076 to Treat Glaucoma; Yale J. Biol. Med., 90, 111-118. Available at:. http://www.drugdevelopment-technology.com (Accessed: April 28, 2015).
[157]
Lu, L.J.; Tsai, J.C.; Liu, J. Novel pharmacologic candidates for treatment of primary open-angle glaucoma. Yale J. Biol. Med., 2017, 90(1), 111-118.
[PMID: 28356898]
[158]
Aerie Pharmaceuticals Reports Positive Results for Lead Candidate AR-13324 in Normotensive Individuals, Available at:. http://glaucomatoday.com (Accessed: April 29, 2015).
[159]
Weiss, M.; Levy, B.; Kopczynski, C.; Haarlem, T.V.; Novack, G. Evaluation of AR-13324, a novel dual mechanism agent, in lowering of IOP in glaucoma and ocular hypertension. Invest. Ophthalmol. Vis. Sci., 2013, 54, 754.
[160]
Bacharach, J.; Dubiner, H.B.; Levy, B.; Kopczynski, C.C.; Novack, G.D. AR-13324-CS202 Study Group. Double-masked, randomized, dose-response study of AR-13324 versus latanoprost in patients with elevated intraocular pressure. Ophthalmology, 2015, 122(2), 302-307.
[http://dx.doi.org/10.1016/j.ophtha.2014.08.022] [PMID: 25270273]
[161]
Aerie Pharmaceuticals Initiates Phase 2b Study of PG324, a Novel Fixed-Combination Product to Treat Patients with Glaucoma or Ocular Hypertension, Available at:. http://www.firstwordpharma.com (Accessed: May 1, 2015).
[162]
Aerie Pharmaceuticals Reports Positive Results for Lead Candidate AR-13324 in Normotensive Individuals Aerie Reaffirms Timeline to Commence Two Phase 3 Studies By Mid- 2014, Available at:. http://investors.aeriepharma.com (Accessed: May 3, 2015).
[163]
Kopczynski, C.C.; Epstein, D.L. Emerging trabecular outflow drugs. J. Ocul. Pharmacol. Ther., 2014, 30(2-3), 85-87.
[http://dx.doi.org/10.1089/jop.2013.0197] [PMID: 24304197]
[164]
Yang, Z.; Wang, J.; Liu, X.; Cheng, Y.; Deng, L.; Zhong, Y. Y-39983 downregulates RhoA/Rho-associated kinase expression during its promotion of axonal regeneration. Oncol. Rep., 2013, 29(3), 1140-1146.
[http://dx.doi.org/10.3892/or.2012.2205] [PMID: 23258382]
[165]
Chen, J.; Runyan, S.A.; Robinson, M.R. Novel ocular antihypertensive compounds in clinical trials. Clin. Ophthalmol., 2011, 5, 667-677.
[http://dx.doi.org/10.2147/OPTH.S15971] [PMID: 21629573]
[166]
Biro, M.; Munoz, M.A.; Weninger, W. Targeting Rho-GTPases in immune cell migration and inflammation. Br. J. Pharmacol., 2014, 171(24), 5491-5506.
[http://dx.doi.org/10.1111/bph.12658] [PMID: 24571448]
[167]
Lavik, E.; Kuehn, M.H.; Kwon, Y.H. Novel drug delivery systems for glaucoma. Eye (Lond.), 2011, 25(5), 578-586.
[http://dx.doi.org/10.1038/eye.2011.82] [PMID: 21475311]

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