Discovery and preclinical development of netarsudil, a novel ocular hypotensive agent for the treatment of glaucoma

Journal of Ocular Pharmacology and Therapeutics

Volumn 34, Issue 1-2, 2018, Pages 40-51

  Lin, Cheng Wen ^a   Sherman, Bryan ^a   Moore, Lori A ^a   Laethem, Carmen L ^a   Lu, Da Wen ^b   Pattabiraman, Padmanabhan P ^c   Rao, Ponugoti Vasantha ^c   Delong, Mitchell A ^a   Kopczynski, Casey C ^a  

^a and Durham   (United States)

^b NATIONAL DEFENSE MEDICAL CENTER   (Taiwan)

^c DUKE UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

glaucoma; intraocular pressure; netarsudil; Rho kinase; trabecular meshwork

Indexed keywords

ACTIN; NETARSUDIL; RHO KINASE; RHO KINASE 1; RHO KINASE 2; RHO KINASE INHIBITOR; TRANSFORMING GROWTH FACTOR BETA2; UNCLASSIFIED DRUG; ANTIHYPERTENSIVE AGENT; AR-13324; BENZOIC ACID; BETA ALANINE; EYE DROPS;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTIHYPERTENSIVE ACTIVITY; ARTICLE; CLINICAL PHARMACOLOGY; CONTROLLED STUDY; CORNEA; DOG; DRUG EFFICACY; DRUG TOLERABILITY; FOCAL ADHESION; GLAUCOMA; HAPLORHINI; HUMAN; HUMAN TISSUE; HYPEREMIA; IC50; IN VITRO STUDY; KINASE ASSAY; LEPORIDAE; NONHUMAN; PIG; PRECLINICAL STUDY; STRESS FIBER; ANIMAL; CHEMICAL STRUCTURE; CHEMISTRY; DISEASE MODEL; DRUG DEVELOPMENT; DRUG TOLERANCE; INTRAOCULAR HYPERTENSION; MALE; PATHOLOGY;

ANIMALS; ANTIHYPERTENSIVE AGENTS; BENZOATES; BETA-ALANINE; DISEASE MODELS, ANIMAL; DOGS; DRUG DISCOVERY; DRUG TOLERANCE; HAPLORHINI; HUMANS; MALE; MOLECULAR STRUCTURE; OCULAR HYPERTENSION; OPHTHALMIC SOLUTIONS; RABBITS; SWINE;

EID: 85038860905     PISSN: 10807683     EISSN: 15577732     Source Type: Journal    
DOI: 10.1089/jop.2017.0023     Document Type: Article

References (46)

1. Alward, W. L. Medical management of glaucoma. N. Engl. J. Med. 339:1298-1307, 1998
2. Casson, R. J., Chidlow, G., Wood, J. P. M., et al. Definition of glaucoma: clinical and experimental concepts. Clin. Exp. Ophthalmol. 40:341-349, 2012.
3. Vrabec, J. P., and Levin, L. A. The neurobiology of cell death in glaucoma. Eye. 21:S11-S14, 2007.
4. Schwartz, K., and Budenz, D. Current management of glaucoma. Curr. Opin. Ophthalmol. 15:119-126, 2004.
5. Stamer, W. D., and Acott, T. S. Current understanding of conventional outflow dysfunction in glaucoma. Curr. Opin. Ophthalmol. 23:135-143, 2012.
6. Grant, W. M. Clinical tonography. Trans. Am. Acad. Ophthalmol. Otolaryngol. 55:774-781, 1951.
7. Bucolo, C., Platania, C. B., Reibaldi, M., Bonfiglio, V., Longo, A., Salomone, S., and Drago, F. Controversies in glaucoma: current medical treatment and drug development. Curr. Pharm. Des. 21:4673-4681, 2015.
8. Bucolo, C., Salomone, S., Drago, F., Reibaldi, M., Longo, A., and Uva, M. G. Pharmacological management of ocular hypertension: current approaches and future prospective. Curr. Opin. Pharmacol. 13:50-55, 2013.
9. Flocks, M., and Zweng, H. C. Studies on the mode of action of pilocarpine on aqueous outflow. Am. J. Ophthalmol. 44:380-386, 1957.
10. Barany, E. H. The mode of action of pilocarpine on outflow resistance in the eye of a primate (Cercopithecus ethiops). Invest. Ophthalmol. 1:712-727, 1962.
11. Donegan, R. K., and Lieberman, R. L. Discovery of molecular therapeutics for glaucoma: challenges, successes, and promising directions. J. Med. Chem. 59:788-809, 2016.
12. Rao, P. V., Pattabiraman, P. P., and Kopczynski, C. Role of the Rho GTPase/Rho kinase signaling pathway in pathogenesis and treatment of glaucoma: bench to bedside research. Exp. Eye. Res. 2016. pii: S0014-483530240-8.
13. Wang, S. K., and Chang, R. T. An emerging treatment option for glaucoma: Rho kinase inhibitors. Clin. Ophthalmol. 8:883-890, 2014.
14. Honjo, M., Tanihara, H., Inatani, M., et al. Effects of rhoassociated protein kinase inhibitor Y-27632 on intraocular pressure and outflow facility. Invest. Ophthalmol. Vis. Sci. 42:137-144, 2001.
15. Thieme, H., Nuskovski, M., Nass, J. U., et al. Mediation of calcium-independent contraction in trabecular meshwork through protein kinase C and rhoA. Invest. Ophthalmol. Vis. Sci. 41:4240-4246, 2000.
16. Rao, P. V., Deng, P. F., Kumar, J., et al. Modulation of aqueous humor outflow facility by the Rho kinase-specific inhibitor Y-27632. Invest. Ophthalmol. Vis. Sci. 42:1029-1037, 2011.
17. Kopczynski, C. C., and Epstein, D. L. Emerging trabecular outflow drugs. J. Ocul. Pharmacol. Ther. 30:85-87, 2014.
18. Garnock-Jones, K. P. Ripasudil: first global approval. Drugs. 74:2211-2215, 2014.
19. Sturdivant, J. M., Royalty, S. M., Lin, C. W., et al. Discovery of the ROCK inhibitor netarsudil for the treatment of openangle glaucoma. Bioorg. Med. Chem. Lett. 26:2475-2480, 2016.
20. Wang, R. F., Williamson, J. E., Kopczynski, C., et al. Effect of 0. 04% AR-13324, a ROCK, and norepinephrine transporter inhibitor, on aqueous humor dynamics in normotensive monkey eyes. J. Glaucoma. 24:51-54, 2015.
21. Li, G., Mukherjee, D., Navarro, I., et al. Visualization of conventional outflow tissue responses to netarsudil in living mouse eyes. Eur. J. Pharmacol. 787:20-31, 2016.
22. Kiel, J. W., and Kopczynski, C. Effect of netarsudil on episcleral venous pressure in Dutch Belted rabbits. J. Ocul. Pharmacol. Ther. 31:146-151, 2015.
23. Ren, R., Li, G., Le, T. D., et al. Netarsudil increases outflow facility in human eyes through multiple mechanisms. Invest. Ophthalmol. Vis. Sci. 57:6197-6209, 2016.
24. Bacharach, J., Dubiner, H. B., Levy, B., et al.; AR-13324-CS202 Study Group. Double-masked, randomized, doseresponse study of AR-13324 versus latanoprost in patients with elevated intraocular pressure. Ophthalmology. 122: 302-307, 2015.
25. Lewis, R. A., Levy, B., Ramirez, N., et al.; PG324-CS201 Study Group. Fixed-dose combination of AR-13324 and latanoprost: a double-masked, 28-day, randomised, controlled study in patients with open-angle glaucoma or ocular hypertension. Br. J. Ophthalmol. 100:339-344, 2016.
26. Katz, J. L., Weiss, M. J., Heah, T., et al. Two Phase 3 studies of the efficacy and safety of AR-13324 Ophthalmic Solution 0. 02%: in Patients with Open Angle Glaucoma and Ocular Hypertension. Invest. Ophthalmol. Vis. Sci. 57: 2016 [ARVO abstract].
27. Rao, P. V., and Epstein, D. L. Rho GTPase/Rho kinase inhibition as a novel target for the treatment of glaucoma. BioDrugs. 21:167-177, 2007.
28. Pattabiraman, P. P., Maddala, R., and Rao, P. V. Regulation of plasticity and fibrogenic activity of trabecular meshwork cells by Rho GTPase signaling. J. Cell. Physiol. 229:927-942, 2014.
29. Pattabiraman, P. P., and Rao, P. V. Mechanistic basis of Rho GTPase-induced extracellular matrix synthesis in trabecular meshwork cells. Am. J. Physiol. Cell Physiol. 298:C749-C763, 2010.
30. Draize, J. H., Woodard, G., and Calvery, H. J. Methods for the study of irritation and toxicity of substances applied topically to the skin and mucous membranes. Pharmacol. Exp. Ther. 82:377-390, 1944.
31. Yau, C. W., and Kaufman, H. E. A medium-term corneal preserving medium (K-Sol). Arch. Ophthalmol. 104:598-601, 1986.
32. Tripathi, R. C., Li, J., Chan, W. F., et al. Aqueous humor in glaucomatous eyes contains an increased level of TGF-beta Exp. Eye Res. 59:723-727, 1994.
33. Fuchshofer, R. The pathogenic role of transforming growth factor-b2 in glaucomatous damage to the optic nerve head. Exp. Eye Res. 93:165-169, 2011.
34. Knipe, R. S., Tager, A. M., and Liao, J. K. The Rho kinases: critical mediators of multiple profibrotic processes and rational targets for new therapies for pulmonary fibrosis. Pharmacol. Rev. 67:103-117, 2015.
35. Moriyama, T., and Nagatoya, K. The Rho-ROCK system as a new therapeutic target for preventing interstitial fibrosis. Drug News Perspect. 17:29-34, 2014.
36. Tsou, P. S., Haak, A. J., Khanna, D., and Neubig, R. R. Cellular mechanisms of tissue fibrosis. 8. Current and future drug targets in fibrosis: focus on Rho GTPaseregulated gene transcription. Am. J. Physiol. Cell. Physiol. 307:C2-C13, 2014.
37. Chang, S. C., and Lee, V. H. Influence of chain length on the in vitro hydrolysis of model ester prodrugs by ocular esterases. Curr. Eye Res. 2:651-656, 1982-1983.
38. Gherezghiher, T., and Koss, M. C. Ocular effects of dipivalyl esters of epinephrine and alpha-methylepinephrine. Exp. Eye Res. 51:537-543, 1990.
39. Rácz, P., Ruzsonyi, M. R., Nagy, Z. T., et al. Maintained intraocular pressure reduction with once-a-day application of a new prostaglandin F2 alpha analogue (PhXA41). An in-hospital, placebo-controlled study. Arch. Ophthalmol. 111:657-661, 1993.
40. Schroeder, C., and Jordan, J. Norepinephrine transporter function and human cardiovascular disease. Am. J. Physiol. Heart Circ. Physiol. 303:H1273-H1282, 2012.
41. Langham, M. E., and Diggs, E. M. Quantitative studies of the ocular response to norepinephrine. Exp. Eye Res. 13: 161-171, 1972.
42. Langham, M. E. The intraocular pressure and the pupillary responses of conscious rabbits to racemic erythroalpha-methylnorepinephrine. Exp. Eye Res. 39:781-790, 1984.
43. Pizzirani, S., and Gong, H. Functional anatomy of the outflow facilities. Vet. Clin. North Am. Small Anim. Pract. 45:1101-1126, 2015.
44. Levy, B., Ramirez, N., Novack, G. D., et al. Ocular hypotensive safety and systemic absorption of AR-13324 ophthalmic solution in normal volunteers. Am. J. Ophthalmol. 159:980-985, 2015.
45. Kopczynski, C., Novack, G. D., Swearingen, D., et al. Ocular hypotensive efficacy, safety and systemic absorption of AR-12286 ophthalmic solution in normal volunteers. Br. J. Ophthalmol. 97:567-572, 2013.
46. Somlyo, A. P., and Somlyo, A. V. Signal transduction by Gproteins, rho-kinase and protein phosphatase to smoothmuscle and non-musclemyosin II. J. Physiol. 522 Pt 2:177-185, 2000.