Abstract
Inhibition of Rho kinase (ROCK) to improve fluid outflow through the trabecular meshwork and lower intraocular pressure is a strategy for the development of new anti-glaucoma agents. Alpha-aryl-beta-amino isoquinoline analogs were identified as potent ROCK inhibitors. Compounds that provided a longer duration of intraocular pressure reduction in Dutch Belted rabbits also inhibited norepinephrine transporter. Ester 60 improved bioavailability of its parent ROCK inhibitor, 29 (Ki=0.2nM) and demonstrated an effective and sustained IOP reduction for 24h after dosing. From these studies, netarsudil (a.k.a. AR-13324) was discovered and is currently in clinical trials for the treatment of glaucoma and ocular hypertension.
Keywords:
AR-13324; Glaucoma; Intraocular pressure (IOP); Rho kinase (ROCK); Trabecular meshwork.
Copyright © 2016 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Benzoates / pharmacology*
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Disease Models, Animal
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Drug Evaluation, Preclinical / methods
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Glaucoma, Open-Angle / drug therapy*
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Humans
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Intraocular Pressure / drug effects
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Molecular Structure
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Norepinephrine Plasma Membrane Transport Proteins / antagonists & inhibitors
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / pharmacology*
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Rabbits
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Serotonin Plasma Membrane Transport Proteins / metabolism
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Structure-Activity Relationship
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Trabecular Meshwork / drug effects
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beta-Alanine / analogs & derivatives*
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beta-Alanine / pharmacology
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rho-Associated Kinases / antagonists & inhibitors*
Substances
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Benzoates
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Norepinephrine Plasma Membrane Transport Proteins
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Protein Kinase Inhibitors
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SLC6A2 protein, human
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SLC6A4 protein, human
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Serotonin Plasma Membrane Transport Proteins
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beta-Alanine
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ROCK2 protein, human
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rho-Associated Kinases
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netarsudil