Details of the Drug

General Information of Drug (ID: DM0LPI9)

Drug Name

Netarsudil

Synonyms

UNII-W6I5QDT7QI; W6I5QDT7QI; Netarsudil mesylate; Netarsudil [USAN]; AR-11324 free base; Netarsudil [USAN:INN]; Netarsudil (USAN/INN); GTPL9322; SCHEMBL16036278; ZINC113149554; AR11324; AR-11324; ester 60; 1628418-15-4

Indication

Disease Entry	ICD 11	Status	REF
Open-angle glaucoma	9C61	Approved	[1]
Glaucoma/ocular hypertension	9C61	Phase 2	[2]

Structure

3D MOL

2D MOL

#Ro5 Violations (Lipinski): 0

Molecular Weight (mw)

453.5

Topological Polar Surface Area (xlogp)

4.6

Rotatable Bond Count (rotbonds)

8

Hydrogen Bond Donor Count (hbonddonor)

2

Hydrogen Bond Acceptor Count (hbondacc)

5

ADMET Property

Half-life: The concentration or amount of drug in body reduced by one-half in 175 minutes [3]
Metabolism: The drug is metabolized via the esterases in the eye to its active metabolite, netarsudil-M1 (or AR-13503) [3]

Chemical Identifiers

Formula: C28H27N3O3
IUPAC Name: [4-[(2S)-3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl]phenyl]methyl 2,4-dimethylbenzoate
Canonical SMILES: CC1=CC(=C(C=C1)C(=O)OCC2=CC=C(C=C2)[C@@H](CN)C(=O)NC3=CC4=C(C=C3)C=NC=C4)C
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
InChIKey: OURRXQUGYQRVML-AREMUKBSSA-N

Cross-matching ID

PubChem CID: 66599893
CAS Number: 1254032-66-0
DrugBank ID: DB13931
TTD ID: D04WYX
ACDINA ID: D01281

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Norepinephrine transporter (NET)	TTAWNKZ	SC6A2_HUMAN	Modulator	[2]
Rho-associated protein kinase (ROCK)	TTMQO60	NOUNIPROTAC	Modulator	[2]
Rho-associated protein kinase 1 (ROCK1)	TTZN7RP	ROCK1_HUMAN	Inhibitor	[1]

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Molecular Interaction Atlas (MIA)

MIA Detail

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Molecular Expression Atlas of This Drug

The Studied Disease

Open-angle glaucoma

ICD Disease Classification

9C61

Molecule Name	Molecule Type	Gene Name	p-value	Fold-Change	Z-score
Norepinephrine transporter (NET)	DTT	SLC6A2	7.05E-01	7.02E-03	0.07

Molecular Expression Atlas (MEA)

MEA Detail

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Drug Inactive Ingredient(s) (DIG) and Formulation(s) of This Drug

DIG

DIG Name	DIG ID	PubChem CID	Functional Classification
Mannitol	E00103	6251	Diluent; Flavoring agent; Lyophilization aid; Plasticizing agent; Tonicity agent
Sodium hydroxide	E00234	14798	Alkalizing agent
Water	E00035	962	Solvent
Boric acid	E00152	7628	Antimicrobial preservative; Buffering agent
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Pharmaceutical Formulation

Formulation Name	Drug Dosage	Dosage Form	Route
Netarsudil 0.2mg/ml solution	0.2mg/ml	Solution	Ophthalmic

Jump to Detail Pharmaceutical Formulation Page of This Drug

References

1	2017 FDA drug approvals.Nat Rev Drug Discov. 2018 Feb;17(2):81-85.
2	Effect of 0.04% AR-13324, a ROCK, and norepinephrine transporter inhibitor, on aqueous humor dynamics in normotensive monkey eyes. J Glaucoma. 2015 Jan;24(1):51-4.
3	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.
4	Augmentation effect of combination therapy of aripiprazole and antidepressants on forced swimming test in mice. Psychopharmacology (Berl). 2009 Sep;206(1):97-107.
5	Treatment of comorbid pain with serotonin norepinephrine reuptake inhibitors. CNS Spectr. 2008 Jul;13(7 Suppl 11):22-6.
6	Invivo antioxidant status: a putative target of antidepressant action. Prog Neuropsychopharmacol Biol Psychiatry. 2009 Mar 17;33(2):220-8.
7	Differential involvement of the norepinephrine, serotonin and dopamine reuptake transporter proteins in cocaine-induced taste aversion. Pharmacol Biochem Behav. 2009 Jul;93(1):75-81.
8	Clinically relevant drug interactions with new generation antidepressants and antipsychotics. Ther Umsch. 2009 Jun;66(6):485-92.
9	2008 FDA drug approvals. Nat Rev Drug Discov. 2009 Feb;8(2):93-6.
10	Antidepressants suppress production of the Th1 cytokine interferon-gamma, independent of monoamine transporter blockade. Eur Neuropsychopharmacol. 2006 Oct;16(7):481-90.
11	Multi-target therapeutics: when the whole is greater than the sum of the parts. Drug Discov Today. 2007 Jan;12(1-2):34-42.
12	The Rho kinase inhibitor SAR407899 potently inhibits endothelin-1-induced constriction of renal resistance arteries. J Hypertens. 2012 May;30(5):980-9.
13	Emerging treatments for pulmonary arterial hypertension. Expert Opin Emerg Drugs. 2006 Nov;11(4):609-19.
14	Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
15	Novel Rho kinase inhibitors with anti-inflammatory and vasodilatory activities. J Pharmacol Exp Ther. 2007 Jan;320(1):89-98.
16	Rho kinase inhibitors: a patent review (2014 - 2016).Expert Opin Ther Pat. 2017 Apr;27(4):507-515.
17	Pharmacological properties of Y-27632, a specific inhibitor of rho-associated kinases. Mol Pharmacol. 2000 May;57(5):976-83.
18	Ocular hypotensive effect of the Rho kinase inhibitor AR-12286 in patients with glaucoma and ocular hypertension. Am J Ophthalmol. 2011 Nov;152(5):834-41.e1.
19	AMA0076, a novel, locally acting Rho kinase inhibitor, potently lowers intraocular pressure in New Zealand white rabbits with minimal hyperemia. Invest Ophthalmol Vis Sci. 2014 Feb 18;55(2):1006-16.
20	A phase I/IIa clinical trial of a recombinant Rho protein antagonist in acute spinal cord injury. J Neurotrauma. 2011 May;28(5):787-96.
21	Effects of Y-39983, a selective Rho-associated protein kinase inhibitor, on blood flow in optic nerve head in rabbits and axonal regeneration of retinal ganglion cells in rats.Curr Eye Res. 2011 Oct;36(10):964-70.
22	Company report (Astex)