NETARSUDIL DIHYDROCHLORIDE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C28H27N3O3.2ClH
Molecular Weight	526.454
Optical Activity	UNSPECIFIED
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

Cl.Cl.CC1=CC=C(C(=O)OCC2=CC=C(C=C2)[C@@H](CN)C(=O)NC3=CC4=C(C=C3)C=NC=C4)C(C)=C1

InChI

InChIKey=LDKTYVXXYUJVJM-FBHGDYMESA-N

InChI=1S/C28H27N3O3.2ClH/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);2*1H/t26-;;/m1../s1

HIDE SMILES / InChI

Molecular Formula	C28H27N3O3
Molecular Weight	453.5323
Charge	0
Count

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	1 / 1
E/Z Centers	0
Optical Activity	UNSPECIFIED

Molecular Formula	ClH
Molecular Weight	36.461
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208254lbl.pdf | https://www.drugbank.ca/drugs/DB13931

Netarsudil ophthalmic solution (Rhopressa) is a Rho kinase inhibitor for the treatment of open-angle glaucoma or ocular hypertension. 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.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Rho-associated protein kinase 2 25 Target ID: CHEMBL2973 Sources: https://www.ncbi.nlm.nih.gov/pubmed/28609185 \| https://www.ncbi.nlm.nih.gov/pubmed/27072905	Inhibitor 8297	1.0 nM [Ki]
Rho-associated protein kinase 1 20 Target ID: CHEMBL3231 Sources: https://www.ncbi.nlm.nih.gov/pubmed/28609185	Inhibitor 8297	1.0 nM [Ki]
Norepinephrine transporter 191 Target ID: CHEMBL222 Sources: https://www.ncbi.nlm.nih.gov/pubmed/27072905	Inhibitor 8297
Rho-associated protein kinase 1 20 Target ID: CHEMBL3231 Sources: https://www.ncbi.nlm.nih.gov/pubmed/27072905	Inhibitor 8297
Rho-associated protein kinase 2 25 Target ID: CHEMBL2973 Sources: https://www.ncbi.nlm.nih.gov/pubmed/27072905	Inhibitor 8297	4.2 nM [IC50]
Protein kinase C eta 10 Target ID: CHEMBL3616 Sources: https://www.ncbi.nlm.nih.gov/pubmed/27072905	Inhibitor 8297
Protein kinase C delta 11 Target ID: CHEMBL2996 Sources: https://www.ncbi.nlm.nih.gov/pubmed/27072905	Inhibitor 8297

Conditions

Condition	Modality	Targets	Highest Phase	Product
Open-angle glaucoma 51 Sources: https://www.ncbi.nlm.nih.gov/pubmed/29199013 https://www.drugs.com/history/rhopressa.html	Primary		Approved 8429	Rhopressa Approved Use RHOPRESSA® (netarsudil ophthalmic solution) 0.02% is a Rho kinase inhibitor indicated for the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension. Launch Date 2017
Ocular hypertension 50 Sources: https://www.ncbi.nlm.nih.gov/pubmed/29199013 https://www.drugs.com/history/rhopressa.html	Primary		Approved 8429	Rhopressa Approved Use RHOPRESSA® (netarsudil ophthalmic solution) 0.02% is a Rho kinase inhibitor indicated for the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension. Launch Date 2017

C_max

Value	Dose	Co-administered	Analyte	Population
1.51 ng/mL DRUG LABEL https://www.ema.europa.eu/en/documents/assessment-report/rhokiinsa-epar-public-assessment-report_en.pdf	0.53 mg/kg 1 times / day multiple, intravenous dose: 0.53 mg/kg route of administration: Intravenous experiment type: MULTIPLE co-administered:		NETARSUDIL METABOLITE AR-13503 unknown	Canis lupus population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
3004 ng × h/mL DRUG LABEL https://www.ema.europa.eu/en/documents/assessment-report/rhokiinsa-epar-public-assessment-report_en.pdf	12.5 mg/kg single, intravenous dose: 12.5 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:		NETARSUDIL METABOLITE AR-13503 plasma	Canis lupus population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
19.5 h DRUG LABEL https://www.ema.europa.eu/en/documents/assessment-report/rhokiinsa-epar-public-assessment-report_en.pdf	unknown, unknown		NETARSUDIL METABOLITE AR-13503 plasma	Oryctolagus cuniculus population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
0.02 % 2 times / day multiple, ophthalmic Highest studied dose Dose: 0.02 %, 2 times / day Route: ophthalmic Route: multiple Dose: 0.02 %, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208254lbl.pdf Page: 2	unhealthy, adult Health Status: unhealthy Condition: open-angle glaucoma or ocular hypertension Age Group: adult Sex: unknown Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208254lbl.pdf Page: 2	Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208254lbl.pdf Page: 2
0.02 % 1 times / day multiple, ophthalmic Recommended Dose: 0.02 %, 1 times / day Route: ophthalmic Route: multiple Dose: 0.02 %, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208254lbl.pdf Page: 6.1	unhealthy, adult Health Status: unhealthy Condition: open-angle glaucoma or ocular hypertension Age Group: adult Sex: unknown Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208254lbl.pdf Page: 6.1	Other AEs: Conjunctival hyperemia, Eye disorders NEC... Other AEs: Conjunctival hyperemia (53%) Eye disorders NEC (20%) Ocular signs and symptoms NEC (5 - 10) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208254lbl.pdf Page: 6.1

AEs

AE	Significance	Dose	Population
Eye disorders NEC	20%	0.02 % 1 times / day multiple, ophthalmic Recommended Dose: 0.02 %, 1 times / day Route: ophthalmic Route: multiple Dose: 0.02 %, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208254lbl.pdf Page: 6.1	unhealthy, adult Health Status: unhealthy Condition: open-angle glaucoma or ocular hypertension Age Group: adult Sex: unknown Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208254lbl.pdf Page: 6.1
Ocular signs and symptoms NEC	5 - 10	0.02 % 1 times / day multiple, ophthalmic Recommended Dose: 0.02 %, 1 times / day Route: ophthalmic Route: multiple Dose: 0.02 %, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208254lbl.pdf Page: 6.1	unhealthy, adult Health Status: unhealthy Condition: open-angle glaucoma or ocular hypertension Age Group: adult Sex: unknown Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208254lbl.pdf Page: 6.1
Conjunctival hyperemia	53%	0.02 % 1 times / day multiple, ophthalmic Recommended Dose: 0.02 %, 1 times / day Route: ophthalmic Route: multiple Dose: 0.02 %, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208254lbl.pdf Page: 6.1	unhealthy, adult Health Status: unhealthy Condition: open-angle glaucoma or ocular hypertension Age Group: adult Sex: unknown Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208254lbl.pdf Page: 6.1

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
		inhibitor 1852

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2C19 1478	CYP 270

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
CYP2C19 1553	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208254Orig1s000ClinPharmR.pdf#page=8 Page: 8.0	yes [Inhibition 10 uM]
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208254Orig1s000ClinPharmR.pdf#page=8 Page: 8.0	yes [Inhibition 10 uM]

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
CYP 270	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208254Orig1s000ClinPharmR.pdf#page=15 Page: 15.0	no

Sourcing

Vendor/Aggregator	ID	URL
AA Blocks	AA01FHG7	https://www.aablocks.com/goods/Goods/detail?id=AA01FHG7
CSNpharm	CSN21168	https://www.csnpharm.com/products/ar-13324-m1-metabolite.html
Chem Scene	CS-0043468	http://www.chemscene.com/CS-0043468.html
Chemspace	CSSS00159268835	https://chem-space.com/CSSS00159268835
MedChem Express	HY-12798C	https://www.medchemexpress.com/AR-13324_M1_metabolite.html
MolPort	MolPort-046-418-075
Smolecule	S519222	http://www.smolecule.com/products/s519222
THE BioTek	bt-259783	https://www.thebiotek.com/product/inhibitors/bt-259783
ZINC	ZINC000113146450	http://zinc15.docking.org/substances/ZINC000113146450

PubMed

Title	Date	PubMed
Netarsudil Increases Outflow Facility in Human Eyes Through Multiple Mechanisms.	2016 Nov 1	27842161
Visualization of conventional outflow tissue responses to netarsudil in living mouse eyes.	2016 Sep 15	27085895
Two Phase 3 Clinical Trials Comparing the Safety and Efficacy of Netarsudil to Timolol in Patients With Elevated Intraocular Pressure: Rho Kinase Elevated IOP Treatment Trial 1 and 2 (ROCKET-1 and ROCKET-2).	2018 Feb	29199013
Discovery and Preclinical Development of Netarsudil, a Novel Ocular Hypotensive Agent for the Treatment of Glaucoma.	2018 Jan/Feb	28609185

Patents

Sample Use Guides

In Vivo Use Guide

RHOPRESSA® (netarsudil ophthalmic solution) 0.02%, for topical ophthalmic use. One drop into the affected eye(s) once daily in the evening.

Route of Administration: Topical

In Vitro Use Guide

Netarsudil inhibited kinases ROCK1 and ROCK2 with a Ki of 1 nM each, disrupted actin stress fibers and focal adhesions in TM cells with IC50s of 79 and 16 nM, respectively, and blocked the profibrotic effects of TGF-β2 in HTM cells.

Substance Class	Chemical Created by `admin` on `Sat Dec 16 10:51:03 GMT 2023` Edited by `admin` on `Sat Dec 16 10:51:03 GMT 2023`
Record UNII	SE030PF6VE
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

NETARSUDIL DIHYDROCHLORIDE

Common Name

English

BENZOIC ACID, 2,4-DIMETHYL-, (4-((1S)-1-(AMINOMETHYL)-2-(6-ISOQUINOLINYLAMINO)-2-OXOETHYL)PHENYL)METHYL ESTER, HYDROCHLORIDE (1:2)

Systematic Name

English

Code System Code Type Description

SMS_ID

100000178117