Netarsudil
Identification
- Summary
Netarsudil is a rho kinase inhibitor used to reduce intraocular pressure in patients with open angle glaucoma or ocular hypertension.
- Brand Names
- Rhopressa, Rocklatan
- Generic Name
- Netarsudil
- DrugBank Accession Number
- DB13931
- Background
A Rho kinase inhibitor with norepinephrine transport inhibitory activity that reduces production of aqueous
As of December 18, 2017 the FDA approved Aerie Pharmaceutical's Rhopressa (netarsudil ophthalmic solution) 0.02% for the indication of reducing elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension. Acting as both a rho kinase inhibitor and a norepinephrine transport inhibitor, Netarsudil is a novel glaucoma medication in that it specifically targets the conventional trabecular pathway of aqueous humour outflow to act as an inhibitor to the rho kinase and norepinephrine transporters found there as opposed to affecting protaglandin F2-alpha analog like mechanisms in the unconventional uveoscleral pathway that many other glaucoma medications demonstrate.
- Type
- Small Molecule
- Groups
- Approved
- Structure
- Weight
- Average: 453.542
Monoisotopic: 453.205241741 - Chemical Formula
- C28H27N3O3
- Synonyms
- (4-((1S)-1-(Aminomethyl)-2-(isoquinolin-6-ylamino)-2-oxoethyl)phenyl)methyl 2,4- dimethylbenzoate
- Netarsudil
- External IDs
- AR-11324 free base
Pharmacology
- Indication
Netarsudil is indicated for the reduction of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension Label.
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Increased intraocular pressure •••••••••••• •••••••••• •••••••• Treatment of Increased intraocular pressure •••••••••••• •••••• •••••••••••• - Contraindications & Blackbox Warnings
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- Pharmacodynamics
Aqueous humour flows out of the eye via two pathways: 1) the conventional trabecular pathway and 2) the unconventional uveoscleral pathway. And, although it has been shown that the conventional trabecular pathway accounts for most aqueous outflow due to various pathologies, most medications available for treating glaucoma target the uveoscleral pathway for treatment and leave the diseased trabecular pathway untreated and unhindered in its progressive deterioration and dysfunction 2.
Netarsudil is subsequently a novel glaucoma medication that is both a rho kinase and norepinephrine transport (NATs)s inhibitor that specifically targets and inhibits rho kinase and NATS found in the conventional trabecular pathway while many of its contemporaries offer therapy that focuses on cell and muscle tissue remodelling 2,3
- Mechanism of action
The medical condition glaucoma is a leading cause of progressive visual impairment and blindness across the world with primary open-angle glaucoma (POAG) being the major type of glaucoma 2.
Elevated intraocular pressure (IOP) resulting from increased resistance to aqueous humor outflow is considered a major risk for the development and progression of POAG, but various clinical studies have demonstrated that the reduction and tight control of IOP can delay or prevent POAG and the vision loss associated with it. Ordinary physiological IOP results from aqueous humor produced by the ocular ciliary body and its outflow through two main outflow pathways: the conventional (trabecular) and the unconventional (uveoscleral) pathways 2.
Under ordinary physiological conditions, diagnostic tracers have shown that the conventional trabecular pathway accounts for up to 90% of aqueous humor outflow. Through this pathway, aqueous humor drains from the anterior chamber sequentially through the uveal and corneoscleral meshwork beams, juxtacanalicular connective tissue (JCT) region, and inner wall (IW) endothelial cells of Schlemm's canal (SC) until finally entering the lumen of SC. From there aqueous humor drains into the collector channels, intravascular plexus, epscleral veins, and finally into the blood circulation 2.
In glaucomatous eyes, elevated IOP is the result of abnormally increased resistance to aqueous outflow in the conventional trabecular pathway due to apparent increases in the contractile tone and stiffness of the trabecular pathway meshwork (TM), changes in extracellular matrix composition, and/or a decrease in the conductance of the IW endothelial cells of SC 2.
Subsequently, as a rho kinase inhibitor, the novelty of netarsudil lies in its ability or specificity to apply its mechanism of action directly and specifically at the diseased TM of the conventional trabecular outflow pathway. In particular, rho kinases are serine/threonine kinases that function as important downstream effectors of Rho GTPase. Such activity in the TM and SC drives actomysin contraction, promotes extracellular matrix production, and increases cell stiffness. Acting as an inhibitor of rho kinase, netarsudil consequently reduces cell contraction, decreases the expression of fibrosis-related proteins, and reduces cell stiffness in the TM and SC cells. As a result, netarsudil has been able to demonstrate increases in trabecular outflow facility, increases in the effective filtration area of the TM, cause expansion of the TM tissue, and dilate episcleral veins 1,2.
Furthermore, netarsudil is also believed to possess inhibitory action against the norepinephrine transporter (NET). Such inhibition of the NET prevents reuptake of norepinephrine at noradrenergic synapses, which results in an increase in the strength and duration of endogenous norepinephrine signaling. As a consequence of this enhanced signaling, norepinephrine-induced vasoconstriction that can reduce blood flow to the ciliary body may subsequently be responsible for a mechanism in which the formation of aqueous humor may be delayed, prolonged, or reduced as well 1.
Target Actions Organism ARho-associated protein kinase 1 inhibitorHumans ARho-associated protein kinase 2 inhibitorHumans ASodium-dependent noradrenaline transporter inhibitorHumans - Absorption
The systemic exposure of netarsudil and its active metabolite, AR-13503, after topical ocular administration of netarsudil opthalmic solution 0.02% once daily (one drop bilaterally in the morning) for eight days in 18 healthy subjects demonstrated no quantifiable plasma concentrations of netarsudil (lower limit of quantitation [LLOQ] 0.100 ng/mL) post dose on Day 1 and Day 8. Only one plasma concentration at 0.11 ng/mL for the active metabolite was observed for one subject on Day 8 at 8 hours post dose Label.
- Volume of distribution
As netarsudil and its active metabolite demonstrate a high degree of protein binding 4, it is expected to exhibit a low volume of distribution.
- Protein binding
The active metabolite of netarsudil, AR-13503 is highly protein bound in plasma, at approximately 60% bound. As AR-13503 is considered to bind less extensively to plasma proteins as its parent netarsudil, the % protein binding of netarsudil may be at least 60% or higher 4.
- Metabolism
After topical ocular dosing, netarsudil is metabolized by esterases in the eye Label,1 to its active metabolite, netarsudil-M1 (or AR-13503) 1.
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- Route of elimination
Clinical studies assessing the in vitro metabolism of netarsudil using corneal tissue from humans, human plasma, and human liver microsomes and microsomal S9 fractions demonstrated that netarsudil metabolism occurs through esterase activity. Subsequent metabolism of netarsudil's esterase metabolite, AR-13503, was not detectable. In fact, esterase metabolism in human plasma was not detected during a 3 hour incubation 4.
- Half-life
The half-life of netarsudil incubated in vitro with human corneal tissue is 175 minutes 1.
- Clearance
The clearance of netarsudil is strongly influenced by its low plasma concetrations following topical administration and absorption and high protein binding in human plasma inn 4.
- Adverse Effects
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- Toxicity
The most common adverse reaction associated with netarsudil dosed once daily in controlled clinical studies was conjunctival hyperemia which was reported by 53% of patients. Other common adverse affects reported (about 20%) include corneal verticillata, instillation site pain, and even conjunctival hemorrhage. Still other reactions include instillation site erythema, corneal staining, blurred vision, increased lacrimiation, erythema of eyelid, and reduced visual acuity being reported by 5-10% of patients in clinical studies Label.
When using multiple dose containers of topical ophthalmic products there is a possibilty of contaminating the containers with agents that may cause bacterial keratitis by patients who in many cases have a concurrent corneal disease or a disruption of the ocular epithelial surface Label.
Although systemic exposure to netarsudil from ocular administration is low, there is no formal available data on the safe use of netarsudil in pregnant women Label.
There is no formal data available on whether significant netarsudil levels could be present in human milk following ocular administration, on the effects on the breastfed enfant, or on the effects on milk production Label.
The safety and effectiveness of using netarsudil in pediatric patients below the age of 18 years have not been established Label.
No overall differences in safety or effectiveness have been observed between elderly and other aduly patients Label.
Long-term studies in animals have not been performed to evaluate the carcinogenic potential of netarsudil. Netarsudil was not mutagenic in the Ames test, in the mouse lymphoma test, or in the in vivo rat micronucleus test. Studies to evaluate the effects of netarsudil on male or female fertility in animals have not been performed Label.
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.Not Available
- Food Interactions
- No interactions found.
Products
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- Product Ingredients
Ingredient UNII CAS InChI Key Netarsudil dihydrochloride SE030PF6VE 1253952-02-1 LDKTYVXXYUJVJM-FBHGDYMESA-N Netarsudil mesylate VL756B1K0U 1422144-42-0 QQDRLKRHJOAQDC-FBHGDYMESA-N - Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Rhokiinsa Solution / drops 200 ?g/ml Ophthalmic Santen Oy 2020-12-16 Not applicable EU Rhopressa Solution / drops 0.200 mg/1mL Ophthalmic; Topical ALCON LABORATORIES, INC. 2017-12-18 Not applicable US - Mixture Products
Name Ingredients Dosage Route Labeller Marketing Start Marketing End Region Image Rocklatan Netarsudil mesylate (0.20 mg/1mL) + Latanoprost (0.05 mg/1mL) Solution / drops Ophthalmic; Topical ALCON LABORATORIES, INC. 2019-03-12 Not applicable US Roclanda Netarsudil mesylate (200 µg/ml) + Latanoprost (50 µg/ml) Solution / drops Ophthalmic Santen Oy 2022-05-04 Not applicable EU Roclanda Netarsudil mesylate (200 µg/ml) + Latanoprost (50 µg/ml) Solution / drops Ophthalmic Santen Oy 2021-01-28 Not applicable EU
Categories
- ATC Codes
- S01EE51 — Latanoprost and netarsudil
- S01EE — Prostaglandin analogues
- S01E — ANTIGLAUCOMA PREPARATIONS AND MIOTICS
- S01 — OPHTHALMOLOGICALS
- S — SENSORY ORGANS
- Drug Categories
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as beta amino acids and derivatives. These are amino acids having a (-NH2) group attached to the beta carbon atom.
- Kingdom
- Organic compounds
- Super Class
- Organic acids and derivatives
- Class
- Carboxylic acids and derivatives
- Sub Class
- Amino acids, peptides, and analogues
- Direct Parent
- Beta amino acids and derivatives
- Alternative Parents
- Phenylacetamides / Aromatic monoterpenoids / Isoquinolines and derivatives / Benzoic acid esters / Bicyclic monoterpenoids / Benzyloxycarbonyls / m-Xylenes / N-arylamides / Benzoyl derivatives / Aralkylamines show 10 more
- Substituents
- Amine / Aralkylamine / Aromatic heteropolycyclic compound / Aromatic monoterpenoid / Azacycle / Benzenoid / Benzoate ester / Benzoic acid or derivatives / Benzoyl / Benzyloxycarbonyl show 26 more
- Molecular Framework
- Aromatic heteropolycyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- W6I5QDT7QI
- CAS number
- 1254032-66-0
- InChI Key
- OURRXQUGYQRVML-AREMUKBSSA-N
- InChI
- InChI=1S/C28H27N3O3/c1-18-3-10-25(19(2)13-18)28(33)34-17-20-4-6-21(7-5-20)26(15-29)27(32)31-24-9-8-23-16-30-12-11-22(23)14-24/h3-14,16,26H,15,17,29H2,1-2H3,(H,31,32)/t26-/m1/s1
- IUPAC Name
- {4-[(1S)-2-amino-1-[(isoquinolin-6-yl)carbamoyl]ethyl]phenyl}methyl 2,4-dimethylbenzoate
- SMILES
- CC1=CC(C)=C(C=C1)C(=O)OCC1=CC=C(C=C1)[C@@H](CN)C(=O)NC1=CC=C2C=NC=CC2=C1
References
- General References
- Lin CW, Sherman B, Moore LA, Laethem CL, Lu DW, Pattabiraman PP, Rao PV, deLong MA, Kopczynski CC: Discovery and Preclinical Development of Netarsudil, a Novel Ocular Hypotensive Agent for the Treatment of Glaucoma. J Ocul Pharmacol Ther. 2017 Jun 13. doi: 10.1089/jop.2017.0023. [Article]
- Ren R, Li G, Le TD, Kopczynski C, Stamer WD, Gong H: Netarsudil Increases Outflow Facility in Human Eyes Through Multiple Mechanisms. Invest Ophthalmol Vis Sci. 2016 Nov 1;57(14):6197-6209. doi: 10.1167/iovs.16-20189. [Article]
- Garcia GA, Ngai P, Mosaed S, Lin KY: Critical evaluation of latanoprostene bunod in the treatment of glaucoma. Clin Ophthalmol. 2016 Oct 18;10:2035-2050. eCollection 2016. [Article]
- FDA Dermatologic and Ophthalmic Drugs Advisory Committee Meeting Briefing Document on Rhopressa (netarsudil ophthalmic solution) 0.02% [Link]
- External Links
- ChemSpider
- 34980598
- 1992864
- ZINC
- ZINC000113149554
- Wikipedia
- Netarsudil
- FDA label
- Download (246 KB)
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 4 Completed Treatment Glaucoma 1 4 Completed Treatment Ocular Hypertension / Open Angle Glaucoma (OAG) 1 4 Not Yet Recruiting Treatment Normal Tension Glaucoma (NTG) 1 3 Completed Prevention Bullous Keratopathy / Fuchs' Endothelial Dystrophy 1 3 Completed Treatment Glaucoma / Ocular Hypertension 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Solution / drops Ophthalmic 200 ?g/ml Solution / drops Ophthalmic 200 MCG/ML Solution / drops Ophthalmic; Topical 0.200 mg/1mL Solution / drops Ophthalmic; Topical Solution / drops Ophthalmic - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US8394826 No 2013-03-12 2030-11-10 US US9096569 No 2015-08-04 2026-07-11 US US8450344 No 2013-05-28 2026-07-11 US US9415043 No 2016-08-16 2034-03-14 US US9931336 No 2018-04-03 2034-03-14 US US9993470 No 2018-06-12 2034-03-14 US US10174017 No 2019-01-08 2030-01-27 US US10532993 No 2020-01-14 2026-07-11 US US10588901 No 2020-03-17 2034-03-14 US US10654844 No 2020-05-19 2030-11-10 US US10882840 No 2021-01-05 2026-07-11 US US11028081 No 2021-06-08 2030-01-27 US US11021456 No 2021-06-01 2026-07-11 US US11197853 No 2021-12-14 2034-03-14 US US11185538 No 2021-11-30 2034-03-14 US US11618748 No 2010-01-27 2030-01-27 US
Properties
- State
- Liquid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.000277 mg/mL ALOGPS logP 3.77 ALOGPS logP 4.73 Chemaxon logS -6.2 ALOGPS pKa (Strongest Acidic) 13.49 Chemaxon pKa (Strongest Basic) 8.69 Chemaxon Physiological Charge 1 Chemaxon Hydrogen Acceptor Count 4 Chemaxon Hydrogen Donor Count 2 Chemaxon Polar Surface Area 94.31 Å2 Chemaxon Rotatable Bond Count 8 Chemaxon Refractivity 134.66 m3·mol-1 Chemaxon Polarizability 51.09 Å3 Chemaxon Number of Rings 4 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-001r-0960400000-da9711938c65169fa0f2 Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-0udj-0930800000-1d055d4465232144ab0a Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-0019-0951500000-416346dac76b975a7d3e Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-0api-0930300000-74770c4016e5064901e3 Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-0aou-3930000000-cecd9acfca993bdea502 Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-0a4i-0900000000-05d895c37fe646d5c43d Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Not Available
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Protein serine/threonine kinase activity
- Specific Function
- Protein kinase which is a key regulator of actin cytoskeleton and cell polarity. Involved in regulation of smooth muscle contraction, actin cytoskeleton organization, stress fiber and focal adhesio...
- Gene Name
- ROCK1
- Uniprot ID
- Q13464
- Uniprot Name
- Rho-associated protein kinase 1
- Molecular Weight
- 158173.545 Da
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Structural molecule activity
- Specific Function
- Protein kinase which is a key regulator of actin cytoskeleton and cell polarity. Involved in regulation of smooth muscle contraction, actin cytoskeleton organization, stress fiber and focal adhesio...
- Gene Name
- ROCK2
- Uniprot ID
- O75116
- Uniprot Name
- Rho-associated protein kinase 2
- Molecular Weight
- 160898.555 Da
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Norepinephrine:sodium symporter activity
- Specific Function
- Amine transporter. Terminates the action of noradrenaline by its high affinity sodium-dependent reuptake into presynaptic terminals.
- Gene Name
- SLC6A2
- Uniprot ID
- P23975
- Uniprot Name
- Sodium-dependent noradrenaline transporter
- Molecular Weight
- 69331.42 Da
References
- Lin CW, Sherman B, Moore LA, Laethem CL, Lu DW, Pattabiraman PP, Rao PV, deLong MA, Kopczynski CC: Discovery and Preclinical Development of Netarsudil, a Novel Ocular Hypotensive Agent for the Treatment of Glaucoma. J Ocul Pharmacol Ther. 2017 Jun 13. doi: 10.1089/jop.2017.0023. [Article]
Drug created at December 18, 2017 21:52 / Updated at February 21, 2021 18:54