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Discovery and Preclinical Development of Netarsudil, a Novel Ocular Hypotensive Agent for the Treatment of Glaucoma

Purpose: Rho-associated protein kinase (ROCK) inhibitors lower intraocular pressure (IOP) by increasing aqueous outflow through the trabecular meshwork (TM). The preclinical characterization of netarsudil, a new ROCK/norepinephrine transporter (NET) inhibitor currently in clinical development, is pr...

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Autores principales: Lin, Cheng-Wen, Sherman, Bryan, Moore, Lori A., Laethem, Carmen L., Lu, Da-Wen, Pattabiraman, Padmanabhan P., Rao, Ponugoti Vasantha, deLong, Mitchell A., Kopczynski, Casey C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Mary Ann Liebert, Inc. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5963640/
https://www.ncbi.nlm.nih.gov/pubmed/28609185
http://dx.doi.org/10.1089/jop.2017.0023
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author Lin, Cheng-Wen
Sherman, Bryan
Moore, Lori A.
Laethem, Carmen L.
Lu, Da-Wen
Pattabiraman, Padmanabhan P.
Rao, Ponugoti Vasantha
deLong, Mitchell A.
Kopczynski, Casey C.
author_facet Lin, Cheng-Wen
Sherman, Bryan
Moore, Lori A.
Laethem, Carmen L.
Lu, Da-Wen
Pattabiraman, Padmanabhan P.
Rao, Ponugoti Vasantha
deLong, Mitchell A.
Kopczynski, Casey C.
author_sort Lin, Cheng-Wen
collection PubMed
description Purpose: Rho-associated protein kinase (ROCK) inhibitors lower intraocular pressure (IOP) by increasing aqueous outflow through the trabecular meshwork (TM). The preclinical characterization of netarsudil, a new ROCK/norepinephrine transporter (NET) inhibitor currently in clinical development, is presented herein. Methods: The kinase inhibitory activity of netarsudil was compared to its esterase metabolite, netarsudil-M1, and 3 other ROCK inhibitors using a commercially available kinase assay kit. Disruption of actin stress fibers was measured in primary porcine TM cells and disruption of focal adhesions in transformed human TM (HTM) cells. Induction of fibrosis markers after exposure to transforming growth factor-β2 (TGF-β2) was conducted in primary HTM cells. Ocular hypotensive activity and tolerability of topical formulations were evaluated in normotensive Dutch Belted rabbits and Formosan Rock monkeys. In vitro corneal metabolism assays were conducted using dog, pig, rabbit, monkey, and human corneas. In vivo ocular pharmacokinetics was studied in Dutch Belted rabbits. Results: Netarsudil inhibited kinases ROCK1 and ROCK2 with a K(i) of 1 nM each, disrupted actin stress fibers and focal adhesions in TM cells with IC(50)s of 79 and 16 nM, respectively, and blocked the profibrotic effects of TGF-β2 in HTM cells. Netarsudil produced large reductions in IOP in rabbits and monkeys that were sustained for at least 24 h after once daily dosing, with transient, mild hyperemia observed as the only adverse effect. Conclusion: Netarsudil is a novel ROCK/NET inhibitor with high potency in biochemical and cell-based assays, an ability to produce large and durable IOP reductions in animal models, and favorable pharmacokinetic and ocular tolerability profiles.
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spelling pubmed-59636402018-05-23 Discovery and Preclinical Development of Netarsudil, a Novel Ocular Hypotensive Agent for the Treatment of Glaucoma Lin, Cheng-Wen Sherman, Bryan Moore, Lori A. Laethem, Carmen L. Lu, Da-Wen Pattabiraman, Padmanabhan P. Rao, Ponugoti Vasantha deLong, Mitchell A. Kopczynski, Casey C. J Ocul Pharmacol Ther Volume 1: Glaucoma IOP, Neuroprotection and Devices Purpose: Rho-associated protein kinase (ROCK) inhibitors lower intraocular pressure (IOP) by increasing aqueous outflow through the trabecular meshwork (TM). The preclinical characterization of netarsudil, a new ROCK/norepinephrine transporter (NET) inhibitor currently in clinical development, is presented herein. Methods: The kinase inhibitory activity of netarsudil was compared to its esterase metabolite, netarsudil-M1, and 3 other ROCK inhibitors using a commercially available kinase assay kit. Disruption of actin stress fibers was measured in primary porcine TM cells and disruption of focal adhesions in transformed human TM (HTM) cells. Induction of fibrosis markers after exposure to transforming growth factor-β2 (TGF-β2) was conducted in primary HTM cells. Ocular hypotensive activity and tolerability of topical formulations were evaluated in normotensive Dutch Belted rabbits and Formosan Rock monkeys. In vitro corneal metabolism assays were conducted using dog, pig, rabbit, monkey, and human corneas. In vivo ocular pharmacokinetics was studied in Dutch Belted rabbits. Results: Netarsudil inhibited kinases ROCK1 and ROCK2 with a K(i) of 1 nM each, disrupted actin stress fibers and focal adhesions in TM cells with IC(50)s of 79 and 16 nM, respectively, and blocked the profibrotic effects of TGF-β2 in HTM cells. Netarsudil produced large reductions in IOP in rabbits and monkeys that were sustained for at least 24 h after once daily dosing, with transient, mild hyperemia observed as the only adverse effect. Conclusion: Netarsudil is a novel ROCK/NET inhibitor with high potency in biochemical and cell-based assays, an ability to produce large and durable IOP reductions in animal models, and favorable pharmacokinetic and ocular tolerability profiles. Mary Ann Liebert, Inc. 2018-03-01 2018-03-01 /pmc/articles/PMC5963640/ /pubmed/28609185 http://dx.doi.org/10.1089/jop.2017.0023 Text en © Cheng-Wen Lin et al. 2018; Published by Mary Ann Liebert, Inc. This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Volume 1: Glaucoma IOP, Neuroprotection and Devices
Lin, Cheng-Wen
Sherman, Bryan
Moore, Lori A.
Laethem, Carmen L.
Lu, Da-Wen
Pattabiraman, Padmanabhan P.
Rao, Ponugoti Vasantha
deLong, Mitchell A.
Kopczynski, Casey C.
Discovery and Preclinical Development of Netarsudil, a Novel Ocular Hypotensive Agent for the Treatment of Glaucoma
title Discovery and Preclinical Development of Netarsudil, a Novel Ocular Hypotensive Agent for the Treatment of Glaucoma
title_full Discovery and Preclinical Development of Netarsudil, a Novel Ocular Hypotensive Agent for the Treatment of Glaucoma
title_fullStr Discovery and Preclinical Development of Netarsudil, a Novel Ocular Hypotensive Agent for the Treatment of Glaucoma
title_full_unstemmed Discovery and Preclinical Development of Netarsudil, a Novel Ocular Hypotensive Agent for the Treatment of Glaucoma
title_short Discovery and Preclinical Development of Netarsudil, a Novel Ocular Hypotensive Agent for the Treatment of Glaucoma
title_sort discovery and preclinical development of netarsudil, a novel ocular hypotensive agent for the treatment of glaucoma
topic Volume 1: Glaucoma IOP, Neuroprotection and Devices
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5963640/
https://www.ncbi.nlm.nih.gov/pubmed/28609185
http://dx.doi.org/10.1089/jop.2017.0023
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