| Size | Price | Stock | Qty |
|---|---|---|---|
| 5mg |
|
||
| 10mg |
|
||
| Other Sizes |
| Targets |
ROCK; norepinephrine transporter (NET)
Rho kinase (ROCK) and norepinephrine transporter (NET). By inhibiting both ROCK and NET, this compound reduces intraocular pressure (IOP) through increased aqueous humor outflow (via ROCK inhibition) and decreased aqueous humor production (via NET inhibition). |
|---|---|
| ln Vitro |
No detailed in vitro activity data for this specific analog. As an analog of AR-13324, it is expected to inhibit ROCK activity in cell-free kinase assays (e.g., using purified ROCK enzymes and peptide substrates) with sub-micromolar IC50 values, and to inhibit norepinephrine uptake in NET-expressing cells.
|
| ln Vivo |
Six hours after a single dose of 0.04% AR-13324 to 7 normal monkey eyes, C was increased (P<0.05) by 53% in drug-treated eyes compared with either contralateral vehicle-treated control eyes or baseline measurements. The IOP measured by pneumatonometer in treated eyes was reduced (P<0.005) by 25% when compared with baseline measurements and by 24% when compared with contralateral vehicle-treated eyes. For 6 hours after a single dose of 0.04% AR-13324, F was reduced (P<0.05) by 20% and 23% when compared with contralateral vehicle-treated eyes and baseline values, respectively.
Conclusions: AR-13324 reduces IOP in normotensive monkey eyes. A dual mechanism of action, increase in tonographic outflow facility, and decrease of aqueous humor flow rates, accounts for the IOP reduction in normotensive monkey eyes.[1]
In normotensive monkey eyes, the original AR-13324 compound at 0.04% reduces IOP via changes in aqueous humor dynamics. This analog is expected to produce similar ocular hypotensive effects. No detailed in vivo data are available for the analog specifically. |
| Enzyme Assay |
Kinase activity assays: Purified ROCK enzyme (ROCK1 or ROCK2) is incubated with ATP and a peptide substrate (e.g., S6 ribosomal protein peptide) in the presence of varying concentrations of AR-13324 analog mesylate. Phosphorylation is measured by luminescence-based kinase assay kits or by Western blot using phospho-specific antibodies.
|
| Cell Assay |
NET inhibition assays: Cells expressing human norepinephrine transporter (e.g., HEK293-NET) are incubated with the compound and [3H]-norepinephrine. After washing to remove unbound ligand, cell-associated radioactivity is measured by scintillation counting to calculate IC50 values for norepinephrine uptake inhibition.
|
| Animal Protocol |
Seven normotensive monkeys were used. Tonographic outflow facility (C) was measured before drug administration and repeated 6 hours after administration of 50 µL (25 µL×2) of 0.04% AR-13324 to 1 eye and an equal volume of vehicle to the contralateral control eye. Baseline aqueous humor flow rates (F) were measured hourly for 6 hours beginning at 10:00 AM on day 1. On day 2, 50 µL (25 µL×2) of 0.04% AR-13324 was applied to 1 eye of each animal and vehicle to the fellow eye at 8:00 AM. Aqueous humor flow rates were measured at the same times as on the baseline day beginning 2 hours after dosing.[1]
In animal models, the compound is typically administered as an ophthalmic solution (e.g., 0.04% in saline) topically to normotensive or hypertensive rabbit or monkey eyes. IOP is measured using a tonometer at multiple time points (0-24 hours) post-instillation. Aqueous humor dynamics may be measured by fluorophotometry. |
| ADME/Pharmacokinetics |
No detailed PK data for this analog. As a small molecule (MW ~631.7 g/mol), it is expected to have good corneal permeability when administered topically. Systemic absorption is minimal due to low dose and local administration. The mesylate salt form enhances aqueous solubility.
|
| Toxicity/Toxicokinetics |
No toxicity data for this analog. The parent compound AR-13324 (netarsudil) has been clinically approved for glaucoma with a favorable safety profile. Ocular side effects in humans include conjunctival hyperemia and corneal verticillata. Standard research safety precautions apply.
|
| References |
|
| Additional Infomation |
Objective: To evaluate the ocular and systemic safety and systemic absorption of AR-13324 in healthy volunteers with normal blood pressure. Design: Open-label, non-controlled, single-arm phase I clinical trial. Methods: Location: Phase I clinical trial center. Subjects: 18 healthy adult volunteers. Intervention or observation procedure: Subjects received 0.02% AR-13324 eye drops once daily in the morning for 8 days. Primary endpoint: Plasma concentrations of AR-13324 and its putative human metabolite AR-13503, and ocular safety parameters. Results: At any time point, plasma AR-13324 concentrations in all subjects did not exceed the lower limit of quantitation (LOQ). Only one subject had an AR-13503 concentration exceeding the LQ (0.11 ng/mL) in one plasma sample (8 hours after administration on day 8). Once-daily morning administration of AR-13324 significantly reduced baseline intraocular pressure by up to 6 mmHg, and this reduction was statistically significant at all time points after administration (P < .001). Except for one subject, all subjects experienced varying degrees of transient conjunctival hyperemia within 8 hours after morning administration. Conclusion: Once-daily morning administration of 0.2% AR-13324 eye drops for 8 days resulted in little or no quantifiable systemic exposure to the parent compound or its presumed metabolites. Clinically and statistically significant reductions in intraocular pressure were observed in these subjects with normal intraocular pressure, which were more pronounced than the common effects of other intraocular pressure-lowering therapies in this population. [2]
AR-13324 analog mesylate is a research analog of the FDA-approved drug netarsudil (Rhopressa). It is not approved for clinical use. The CAS number is 2095432-73-6. Strictly for research purposes to study ROCK and NET inhibition in ocular and cardiovascular contexts. |
| Molecular Formula |
C29H33N3O9S2
|
|---|---|
| Molecular Weight |
631.72
|
| Exact Mass |
535.1777
|
| CAS # |
2095432-73-6
|
| Related CAS # |
Netarsudil dimesylate;1422144-42-0;Netarsudil hydrochloride;1253952-02-1
|
| PubChem CID |
171921137
|
| Appearance |
Light brown to brown Liquid
|
| Hydrogen Bond Donor Count |
3
|
| Hydrogen Bond Acceptor Count |
8
|
| Rotatable Bond Count |
7
|
| Heavy Atom Count |
38
|
| Complexity |
756
|
| Defined Atom Stereocenter Count |
1
|
| SMILES |
CC1=CC(=C(C=C1)C(=O)OC2=CC=C(C=C2)[C@@H](CN)C(=O)NC3=CC4=C(C=C3)C=NC=C4)C.CS(=O)(=O)O.CS(=O)(=O)O
|
| InChi Key |
MPAAEFZQVJRGLO-VQIWEWKSSA-N
|
| InChi Code |
InChI=1S/C27H25N3O3.CH4O3S/c1-17-3-10-24(18(2)13-17)27(32)33-23-8-5-19(6-9-23)25(15-28)26(31)30-22-7-4-21-16-29-12-11-20(21)14-22;1-5(2,3)4/h3-14,16,25H,15,28H2,1-2H3,(H,30,31);1H3,(H,2,3,4)/t25-;/m1./s1
|
| Chemical Name |
[4-[(2S)-3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl]phenyl] 2,4-dimethylbenzoate;methanesulfonic acid
|
| Synonyms |
2095432-73-6; Benzoic acid, 2,4-dimethyl-, 4-[(1S)-1-(aminomethyl)-2-(6-isoquinolinylamino)-2-oxoethyl]phenyl ester, compd. with methanesulfonate (1:2)
|
| HS Tariff Code |
2934.99.9001
|
| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
DMSO :≥ 28 mg/mL (~44.32 mM)
|
|---|---|
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.5830 mL | 7.9149 mL | 15.8298 mL | |
| 5 mM | 0.3166 mL | 1.5830 mL | 3.1660 mL | |
| 10 mM | 0.1583 mL | 0.7915 mL | 1.5830 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.
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
