Identification

Name
Netarsudil
Accession Number
DB13931
Type
Small Molecule
Groups
Approved
Description

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.

Structure
Thumb
Synonyms
  • (4-((1S)-1-(Aminomethyl)-2-(isoquinolin-6-ylamino)-2-oxoethyl)phenyl)methyl 2,4- dimethylbenzoate
External IDs
AR-11324 free base
Product Ingredients
IngredientUNIICASInChI Key
Netarsudil dihydrochlorideSE030PF6VE1253952-02-1LDKTYVXXYUJVJM-FBHGDYMESA-N
Netarsudil mesylateVL756B1K0U1422144-42-0QQDRLKRHJOAQDC-FBHGDYMESA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
RhopressaSolution / drops0.285 mg/1mLOphthalmic; TopicalAerie Pharmaceuticals Inc.2017-12-18Not applicableUs
Categories
UNII
W6I5QDT7QI
CAS number
1254032-66-0
Weight
Average: 453.542
Monoisotopic: 453.205241741
Chemical Formula
C28H27N3O3
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

Pharmacology

Indication

Netarsudil is indicated for the reduction of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension [Label].

Associated Conditions
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].

TargetActionsOrganism
ARho-associated protein kinase 1
inhibitor
Human
ARho-associated protein kinase 2
inhibitor
Human
Asolute carrier family 6 member 2
inhibitor
Human
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] to its active metabolite, netarsudil-M1 (or AR-13503) [1].

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].

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].

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

General References
  1. 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. [PubMed:28609185]
  2. 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. [PubMed:27842161]
  3. 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. [PubMed:27799730]
  4. FDA Dermatologic and Ophthalmic Drugs Advisory Committee Meeting Briefing Document on Rhopressa (netarsudil ophthalmic solution) 0.02% [Link]
External Links
ChemSpider
34980598
Wikipedia
Netarsudil
FDA label
Download (246 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentHealthy Volunteers1
1CompletedTreatmentHealthy Volunteers / Normal Volunteers1
2Active Not RecruitingTreatmentPrimary Open Angle Glaucoma or Ocular Hypertension1
2CompletedTreatmentOcular Hypertension / Open Angle Glaucoma (OAG)4
2CompletedTreatmentPrimary Open Angle Glaucoma or Ocular Hypertension1
3CompletedTreatmentGlaucoma / Ocular Hypertension1
3CompletedTreatmentOcular Hypertension / Open-angle Glaucoma (OAG)5
3RecruitingPreventionBullous Keratopathy / Fuchs' Endothelial Dystrophy1
Not AvailableNot Yet RecruitingTreatmentHigh Blood Pressure (Hypertension)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Solution / dropsOphthalmic; Topical0.285 mg/1mL
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US8394826No2010-11-102030-11-10Us
US9096569No2006-07-112026-07-11Us
US8450344No2006-07-112026-07-11Us
US9415043No2014-03-142034-03-14Us
US9931336No2014-03-142034-03-14Us

Properties

State
Liquid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.000277 mg/mLALOGPS
logP3.77ALOGPS
logP4.73ChemAxon
logS-6.2ALOGPS
pKa (Strongest Acidic)13.49ChemAxon
pKa (Strongest Basic)8.69ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area94.31 Å2ChemAxon
Rotatable Bond Count8ChemAxon
Refractivity134.66 m3·mol-1ChemAxon
Polarizability51.09 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Taxonomy

Classification
Not classified

Targets

Kind
Protein
Organism
Human
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
Human
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
3. solute carrier family 6 member 2
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
References
  1. 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. [PubMed:28609185]

Drug created on December 18, 2017 14:52 / Updated on October 01, 2018 16:54