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5mg |
Ripasudil (also known as K-115) is potent and selective ROCK inhibitor with IC50 of 51 nM and 19 nM for ROCK1 and ROCK2, respectively, it is used for the treatment of glaucoma and ocular hypertension. Ripasudil, K-115, is a potent ROCK inhibitor. It is approved for use in Japan as a 0.4% ophthalmic solution. In rabbits, topical instillation of K-115 significantly reduced IOP in a dose-dependent manner.
ln Vitro |
Ripasudil (K-115) is a strong inhibitor of ROCK with IC50 values of 19 and 51 nM for ROCK2 and ROCK1, respectively. Ripasudil exhibits mild inhibitory effects on CaMKIIα, PKACα, and PKC, as evidenced by its respective IC50 values of 370 nM, 2.1 μM, and 27 μM [1]. In cultivated trabecular meshwork (TM) cells, ripasudil (K-115; 1, 10 μM) produces cytoskeletal alterations such as cell rounding, shrinkage, and a decrease in actin bundles. In Schlemm's canal endothelial (SCE) cell monolayers, ripasudil (5 μM) dramatically lowers transendothelial electrical resistance (TEER) and raises FITC-dextran permeability [2].
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ln Vivo |
At concentrations between 0.1% and 0.4% in monkey eyes and 0.0625% to 0.5% in rabbit eyes, respectively, dipasudil (K-115) lowers intraocular pressure (IOP) in a concentration-dependent manner[1]. Following nerve crush (NC), retinal ganglion cells (RGCs) exhibit a neuroprotective effect from dipasudil (K-115; 1 mg/kg, po daily). Additionally, in mice, ripasudil prevents oxidative stress brought on by axonal injury. The time-dependent production of ROS in RGCs following NC injury is suppressed by dipasudil [3].
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Animal Protocol |
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ADME/Pharmacokinetics |
Absorption, Distribution and Excretion
Riapsudil is cleared by the kidneys at a rate of 7.112L/h. Ripasudil has a renal clearance of 7.112 L/h. Biological Half-Life The half life of Ripasudil is 0.455 hrs. |
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Toxicity/Toxicokinetics |
Protein Binding
The plasma protein binding rate of Ripasudil is 55.4-59.8% |
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References |
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Additional Infomation |
Ripasudil is a member of isoquinolines.
Ripasudil, as hydrochloride hydrate (K-115), is a specifc Rho-associated coiled-coil containing protein kinase (ROCK) inhibitor used for the treatment of glaucoma and ocular hypertension. It was first approved for treatment in Japan in September 2014. This medication is available in the form of a 0.4% eye drop solution under the brand name Glanatec. Ripasudil is a well tolerated medication that is used when other drugs have been proven to be non-effective or cannot be administered. Drug Indication Ripasudil has been proven to be effective in the twice daily treatment of glaucoma and ocular hypertension. It is currently in studies to be approved for both diabetic retinopathy and diabetic macular oedema. Treatment of corneal dystrophy Mechanism of Action Ripasudil is a highly selective and potent Rho-associated coiled/coil-containing kinase protein (ROCK) inhibitor. Rho-kinase (ROCK) is an effector protein of Rho which binds with Rho to form a Rho/Rho-kinase complex. This complex then regulates many physiological functions including smooth muscle contractions, chemotaxis, neural growth and gene expression. ROCK comes in 2 isoforms: ROCK-1 and ROCK-2 and these two isoforms are distributed widely in our tissues including ocular tissues such as the iris, retina, trabecular meshwork and ciliary muscles. Atypical regulation of ROCK levels is involved in the pathogenesis of diseases such as glaucoma, ocular hypertension, cataracts and other retinal disorders. Ripasudil acts as very highly selective and potent inhibitor with an IC50 of Ripasudil with ROCK-1 of 0.051 umol/L and with ROCK-2 of 0.019 umol/L. ROCK inhibitors have efficacy in reducing IOP by acting on the trabecular meshwork in the eye directly to increase conventional outflow through the Schlemm’s canal. Ripasudil will inhibit ROCK and induce cytoskeletal changes including the retraction and rounding of cell bodies and cause disruption of actin bundles in this trabecular meshwork. This can reduce the compaction of trabecular meshwork tissue and eventually result in increased aqueous outflow in the eye and reduced resistance to fluid flow. Thus, Ripasudil is effective by inducing cytoskeletal changes which are depending on ROCK inhibition. Ripasudil decreases IOP by increasing outflow facility along with modulating the behavior of trabecular meshwork cells and Schlemm’s canal endothelial (SCE) cell permeability along with a disruption of the tight junction. When Ripasudil is used in combination with prostaglandin analogues it results in increased uveoscleral outflow and when used in combination with beta blockers it results in reduced aqueous production. Pharmacodynamics Ripasudil has high intraocular permeability and works by decreasing intraocular pressure (IOP) in a dose-dependent manner and increasing flow facility. The maximum reduction of IOP occurs after 1 to 2 hours. |
Molecular Formula |
C₁₅H₁₈FN₃O₂S
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Molecular Weight |
323.39
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Exact Mass |
323.11
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CAS # |
223645-67-8
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Related CAS # |
Ripasudil;887375-67-9
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PubChem CID |
9863672
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Appearance |
Typically exists as solid at room temperature
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Density |
1.3±0.1 g/cm3
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Boiling Point |
497.2±55.0 °C at 760 mmHg
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Flash Point |
254.5±31.5 °C
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Vapour Pressure |
0.0±1.3 mmHg at 25°C
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Index of Refraction |
1.589
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LogP |
1.72
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Hydrogen Bond Donor Count |
1
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Hydrogen Bond Acceptor Count |
6
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Rotatable Bond Count |
2
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Heavy Atom Count |
22
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Complexity |
482
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Defined Atom Stereocenter Count |
1
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SMILES |
FC1=CN=CC2=C1C(S(N3CCCNC[C@@H]3C)(=O)=O)=CC=C2
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InChi Key |
QSKQVZWVLOIIEV-NSHDSACASA-N
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InChi Code |
InChI=1S/C15H18FN3O2S/c1-11-8-17-6-3-7-19(11)22(20,21)14-5-2-4-12-9-18-10-13(16)15(12)14/h2,4-5,9-11,17H,3,6-8H2,1H3/t11-/m0/s1
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Chemical Name |
4-fluoro-5-[[(2S)-2-methyl-1,4-diazepan-1-yl]sulfonyl]isoquinoline
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Synonyms |
K-115 free baseK 115K115K-115
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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 |
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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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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 | 3.0922 mL | 15.4612 mL | 30.9224 mL | |
5 mM | 0.6184 mL | 3.0922 mL | 6.1845 mL | |
10 mM | 0.3092 mL | 1.5461 mL | 3.0922 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.