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].

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].

Absorption, Distribution and Excretion
Ripasudil is cleared by the kidneys at a rate of 7.112 L/h. The renal clearance of ribasudil is 7.112 L/h. Biological Half-Life The half-life of ribasudil is 0.455 h.

Protein Binding
Ripasudin's plasma protein binding rate is 55.4-59.8%.

[1]. Effects of K-115, a rho-kinase inhibitor, on aqueous humor dynamics in rabbits. Curr Eye Res. 2014 Aug;39(8):813-22.

[2]. Effects of K-115 (Ripasudil), a novel ROCK inhibitor, on trabecular meshwork and Schlemm's canal endothelial cells. Sci Rep. 2016 Jan 19;6:19640.

[3]. The novel Rho kinase (ROCK) inhibitor K-115: a new candidate drug for neuroprotective treatment in glaucoma. Invest Ophthalmol Vis Sci. 2014 Oct 2;55(11):7126-36.

Ripasudil belongs to the isoquinoline class of drugs. Ripasudil, existing as hydrochloride hydrate (K-115), is a specific Rho-associated coiled-coil kinase (ROCK) inhibitor used to treat glaucoma and ocular hypertension. It was first approved for treatment in Japan in September 2014. The drug is marketed as a 0.4% eye drop under the brand name Glanatec. Ripasudil is well-tolerated and suitable for use in cases where other medications are ineffective or unavailable. Drug Indications Ripasudil has been proven effective in treating glaucoma and ocular hypertension, administered twice daily. Current research is underway for approval in the treatment of diabetic retinopathy and diabetic macular edema. Treatment of Corneal Dystrophy Mechanism of Action Ripasudil is a highly selective and potent Rho-associated coiled/coil kinase (ROCK) inhibitor. ROCK is an effector protein of Rho, which binds to Rho to form the Rho/Rho kinase complex. This complex regulates a variety of physiological functions, including smooth muscle contraction, chemotaxis, nerve growth, and gene expression. There are two subtypes of ROCK: ROCK-1 and ROCK-2, which are widely distributed in various ocular tissues, including the iris, retina, trabecular meshwork, and ciliary muscle. ROCK levels are closely related to the pathogenesis of diseases such as glaucoma, intraocular hypertension, cataracts, and other retinal disorders. Ripasudil is a highly selective and potent ROCK inhibitor with an IC50 of 0.051 μmol/L for ROCK-1 and 0.019 μmol/L for ROCK-2. Ripasudil effectively lowers intraocular pressure by directly acting on the trabecular meshwork, increasing the normal outflow of aqueous humor through Schlem's canals. ROCK inhibitors suppress ROCK and induce cytoskeletal alterations, including cell body retraction and rounding, and disruption of actin bundles in the trabecular meshwork. Ripasudil reduces the compaction of the trabecular meshwork, ultimately leading to increased aqueous humor outflow and reduced aqueous humor flow resistance. Therefore, ribasudil exerts its effect by inducing ROCK-inhibition-dependent cytoskeletal alterations. Ripasudil lowers intraocular pressure by increasing aqueous humor outflow, modulating the permeability of trabecular meshwork cells and Schlemm's tubule endothelial cells (SCEs), and disrupting tight junctions. Ripasudil, when used in combination with prostaglandin analogues, increases uveal-scleral outflow, and when used in combination with beta-blockers, it reduces aqueous humor production.

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Pharmacodynamics
Ripasudil has high intraocular permeability, and its mechanism of action is through dose-dependent reduction of intraocular pressure and increase of aqueous humor outflow. The maximum reduction in intraocular pressure occurs 1 to 2 hours after administration.

C₁₅H₁₈FN₃O₂S

323.39

323.11

223645-67-8

Ripasudil;887375-67-9

9863672

White to off-white solid powder

1.3±0.1 g/cm3

497.2±55.0 °C at 760 mmHg

254.5±31.5 °C

0.0±1.3 mmHg at 25°C

1.589

1.72

1

6

2

22

482

1

FC1=CN=CC2=C1C(S(N3CCCNC[C@@H]3C)(=O)=O)=CC=C2

QSKQVZWVLOIIEV-NSHDSACASA-N

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

4-fluoro-5-[[(2S)-2-methyl-1,4-diazepan-1-yl]sulfonyl]isoquinoline

K-115 free baseK 115K115K-115

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

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

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.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*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).

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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)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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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).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)