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Purity: ≥98%
Netarsudil mesylate, the mesylate salt form of Netarsudil (formerly known as AR-13324; Rhopressa), is novel ROCK inhibitor with Ki of 0.2-10.3 nM. Additionally, it suppresses norepinephrine transport activity, which may lessen aqueous humor production. The FDA approved Netarsudil in 2018 to treat ocular hypertension and glaucoma.
| Targets |
Rho-associated protein kinas/ROCK; norepinephrine transporter/NET
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| ln Vitro |
Netarsudil has been demonstrated in prior research to be able to cause TM cells' extracellular matrix composition to alter, focal adhesions to disappear, actin stress fiber loss, and cell shape alterations.
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| ln Vivo |
Netarsudil effectively lowers intraocular pressure (IOP) in the eyes of both humans and non-human primates by primarily targeting cells in the conventional outflow tract. Furthermore, it has been demonstrated that netarsudil lowers episcleral venous pressure in rabbit eyes and increases outflow facility in non-human primate eyes[2].
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| Enzyme Assay |
Netarsudil (formerly known as AR-13324) is an inhibitor of ROCK having a Ki of 0.2-10.3 nM. Moreover, it suppresses norepinephrine transport activity, which may lessen aqueous humor production.
A total of 23 ROCK structures were found in the PDB. The maximum and minimum resolutions were 3.4 Å and 2.93 Å, respectively. Seven ROCK-I and two ROCK-II non-redundant structures were selected for the binding assay. Out of 46 compounds tested (20 isoquinolines, 15 aminofurazan, 6 benzodiazepine, 4 indazoles, and 1 amide), 34 presented a significantly higher docking score for ROCK-1, when compared to Y-27632 (p < 0.0001). All ROCKi classes presented a stronger mean docking score than Y-27632 (p < 0.0001). The frequency of compounds presenting highest docking score was higher in the isoquinoline, aminofurazan, and benzodiazepine classes for ROCK-I; and in isoquinolines and amides for ROCK-II (Supplementary Figure S2A). The top ten compounds that presented the highest mean docking scores for ROCK-I and II are shown in Supplementary Figure S2B. The isoquinoline class represented 70% of the drugs within the top ten highest docking scores, with three compounds presenting a docking score stronger than 12. There were no significant differences among ROCK inhibitors other than Y-27632. Interestingly, in silico molecular docking simulation showed that the majority of the molecules evaluated, specifically fromthe isoquinoline, benzodiazepine, and amide classes, had higher binding strength for ROCK-1 and ROCK-2 than Y-27632 (Supplementary Figure S2B). In silico molecular docking simulation was performed, coupling isoforms found for AR-13324 and Y-27632 inhibitors in the PDB to high-resolution ROCK proteins. All of the AR-13324 molecules tested had a higher docking score for ROCK-1 and -2 than Y-27632. In addition, PDB molecules from the isoquinoline, benzodiazepine, and amide classes also showed superior mean docking scores than Y-27632 isoforms (Supplementary Figure S2B)[4]. |
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| Cell Assay |
Prior research revealed that netarsudil could cause TM cells' extracellular matrix composition to alter, as well as the loss of focal adhesions, actin stress fibers, and cell shape.
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| Animal Protocol |
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| ADME/Pharmacokinetics |
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. 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. Volume of Distribution As netarsudil and its active metabolite demonstrate a high degree of protein binding, it is expected to exhibit a low volume of distribution. 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. Metabolism / Metabolites After topical ocular dosing, netarsudil is metabolized by esterases in the eye to its active metabolite, netarsudil-M1 (or AR-13503). Biological Half-Life The half-life of netarsudil incubated *in vitro with human corneal tissue is 175 minutes. |
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| Toxicity/Toxicokinetics |
Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation No information is available on the use of netarsudil during breastfeeding. Because netarsudil poorly absorbed by the mother after administration to the eye, it is unlikely to adversely affect the breastfed infant. Until more data become available, netarsudil should be used with caution during breastfeeding, especially while nursing a newborn or preterm infant. To decrease the amount of drug that reaches the breastmilk after using eye drops, place pressure over the tear duct by the corner of the eye for 1 minute or more, then remove the excess solution with an absorbent tissue. ◉ Effects in Breastfed Infants Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. |
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| References | |||
| Additional Infomation |
See also: Netarsudil (has active moiety); Latanoprost; netarsudil mesylate (component of).
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| Molecular Formula |
C30H35N3O9S2
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| Molecular Weight |
645.74
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| Exact Mass |
645.181
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| Elemental Analysis |
C, 55.80; H, 5.46; N, 6.51; O, 22.30; S, 9.93
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| CAS # |
1422144-42-0
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| Related CAS # |
Netarsudil hydrochloride;1253952-02-1;AR-13324 analog mesylate; 1422144-42-0; 1254032-66-0
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| PubChem CID |
90410375
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| Appearance |
White to yellow solid powder
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
11
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
44
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| Complexity |
770
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| Defined Atom Stereocenter Count |
1
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| SMILES |
S(C)(=O)(=O)O.S(C)(=O)(=O)O.O=C([C@@H](CN)C1C=CC(COC(C2C=CC(C)=CC=2C)=O)=CC=1)NC1C=CC2C=NC=CC=2C=1
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| InChi Key |
QQDRLKRHJOAQDC-FBHGDYMESA-N
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| InChi Code |
InChI=1S/C28H27N3O3.2CH4O3S/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;2*1-5(2,3)4/h3-14,16,26H,15,17,29H2,1-2H3,(H,31,32);2*1H3,(H,2,3,4)/t26-;;/m1../s1
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| Chemical Name |
[4-[(2S)-3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl]phenyl]methyl 2,4-dimethylbenzoate;methanesulfonic acid
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (3.87 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (3.87 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (3.87 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.5486 mL | 7.7431 mL | 15.4861 mL | |
| 5 mM | 0.3097 mL | 1.5486 mL | 3.0972 mL | |
| 10 mM | 0.1549 mL | 0.7743 mL | 1.5486 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
Netarsudil lowered intraocular pressure (IOP) in both pigmented and nonpigmented mice.
Netarsudil mesylate enhanced IOP recovery in living mouse eyes.Eur J Pharmacol.2016 Sep 15;787:20-31. |
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Netarsudil mesylate increased outflow facility in perfused mouse eyes ex vivo.Eur J Pharmacol.2016 Sep 15;787:20-31. |
Enhanced tracer deposition in outflow tissues of living mice subjected to netarsudil mesylate treatment.Eur J Pharmacol.2016 Sep 15;787:20-31. |
Netarsudil-induced changes in conventional outflow tissue morphology of living mice visualized by optical coherence tomography (OCT).Eur J Pharmacol.2016 Sep 15;787:20-31. |
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Netarsudil increased cross-sectional area of Schlemms canal (SC) lumen in living mice with elevated intraocular pressure (IOP) visualized by optical coherence tomography (OCT).Eur J Pharmacol.2016 Sep 15;787:20-31. |
Netarsudil-induced changes in flow area and intensity in scleral vessels visualized on OCT speckle variance images.Eur J Pharmacol.2016 Sep 15;787:20-31. |
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