K-115

Selective Rho kinase inhibitor CAS# 887375-67-9

K-115

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K-115

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Chemical Properties of K-115

Cas No. 887375-67-9 SDF Download SDF
PubChem ID 11625386 Appearance Powder
Formula C15H23ClFN3O4S M.Wt 395.88
Type of Compound N/A Storage Desiccate at -20°C
Synonyms Ripasudil
Solubility H2O : ≥ 50 mg/mL (126.30 mM)
*"≥" means soluble, but saturation unknown.
Chemical Name 4-fluoro-5-[[(2S)-2-methyl-1,4-diazepan-1-yl]sulfonyl]isoquinoline;dihydrate;hydrochloride
SMILES CC1CNCCCN1S(=O)(=O)C2=CC=CC3=CN=CC(=C32)F.O.O.Cl
Standard InChIKey CMDJNMACGABCKQ-XVSRHIFFSA-N
Standard InChI InChI=1S/C15H18FN3O2S.ClH.2H2O/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;1H;2*1H2/t11-;;;/m0.../s1
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of K-115

DescriptionK-115 is a specific inhibitor of ROCK, with IC50s of 19 and 51 nM for ROCK2 and ROCK1, respectively.In Vitro:K-115 is a potent inhibitor of ROCK, with IC50s of 19 and 51 nM for ROCK2 and ROCK1, respectively. K-115 also shows less potent inhibitory activities against CaMKIIα, PKACα and PKC, with IC50s of 370 nM, 2.1 μM and 27 μM, respectively[1]. K-115 (1, 10 μM) induces cytoskeletal changes, including retraction and cell rounding and reduced actin bundles of cultured trabecular meshwork (TM) cells. K-115 (5 μM) sifnificantly reduces transendothelial electrical resistance (TEER), and increases FITC-dextran permeability in Schlemm’s canal endothelial (SCE) cell monolayers[2].In Vivo:K-115 reduces intraocular pressure (IOP) in a concentration-dependent manner at concentrations between 0.1% and 0.4% in monkey eyes and 0.0625% to 0.5% in rabbit eyes, respectively[1]. K-115 (1 mg/kg, p.o. daily) shows a neuroprotective effect on retinal ganglion cells (RGCs) after nerve crush (NC). K-115 also inhibits the oxidative stress induced by axonal injury in mice. K-115 suppresses the time-dependent production of ROS in RGCs after NC injury[3]

References:
[1]. Isobe T, et al. Effects of K-115, a rho-kinase inhibitor, on aqueous humor dynamics in rabbits. Curr Eye Res. 2014 Aug;39(8):813-22. [2]. Kaneko Y, et al. 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]. Yamamoto K, et al. 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.

Protocol

Kinase Assay [1]
ROCK 1 (0.75 ng/mL) and ROCK 2 (0.5 ng/mL) are incubated with various concentrations of K-115, Y-27632, or HA-1077 at 25°C for 90 min in 50 mM Tris-HCl buffer (pH 7.5) containing 100 mM KCl, 10 mM MgCl2, 0.1 mM EGTA, 30 mM Long S6 Kinase Substrate peptide, and 1 mM ATP in a total volume of 40 mL. PKACa, PKC, and CaMKIIa are also incubated with various concentrations of K-115, Y-27632, or HA-1077. PKACa (0.0625 ng/mL) is incubated at 25°C for 30 min in 40 mM Tris-HCl buffer (pH 7.5) containing 20 mM MgCl2, 1 mg/ mL BSA, 5 mM Kemptide peptide substrate, and 1 mM ATP in a total volume of 40 mL. PKC (0.025 ng/mL) is incubated at 25°C for 80 min in 20 mM Tris-HCl buffer (pH 7.5) containing 20 mM MgCl2, 0.4 mM CaCl2, 0.1 mg/mL BSA, 0.25 mM EGTA, 25 ng/mL phosphatidylserine, 2.5 ng/mL diacylglycerol, 0.0075% Triton-X-100, 25 mM DTT, 10 mM Neurogranin (28-43) peptide substrate, and 1 mM ATP in a total volume of 40 mL. CaMKIIa (0.025 ng/mL) is incubated at 25°C for 90 min in 50 mM Tris-HCl buffer (pH 7.5) containing 10 mM MgCl2, 2 mM CaCl2, 0.04 mg/mL BSA, 16 mg/mL purified calmodulin from bovine testis, 500 mM DTT, 50 mM Autocamitide 2, and 1 mM ATP in a total volume of 40 mL. After incubation, 40 mL of KinaseGlo Luminescent Kinase Assay solution is added, and allowed to remain at 25°C for 10 min, and Relative Light Units (RLU) are measured using a luminometer. The RLU without test compound is set as 100% (Control value), and that without enzyme and compound is set as 0% (Normal value). The reaction rate (% of control) is then calculated from the RLU with addition of each concentration of test compounds, and the 50% inhibitory concentrations (IC50) are determined by logistic regression analysis using SAS[1].

Cell Assay [2]
Trabecular meshwork (TM) cells are plated on 6 well plates at a density of 1 × 104 cells per well in DMEM containing 10% FBS. Following overnight culture, when cells have reached semiconfluence, 1 or 10 μM of K-115, 10 μM of Y-27632, or 10 μM of fasudil are added to culture wells. PBS is used as a control vehicle. After 60 min, drug solutions are removed and replaced with DMEM containing 10% FBS. Cells are observed by phase-contrast microscopy and photographed 60 min after drug application and 2 h after drug removal. For immunohistochemistry, TM cells are plated on gelatin-coated 8 well chamber slides at a density of 1 × 104 cells per well in DMEM containing 10% FBS. After overnight culture, when cells reach semiconfluence, cell are incubated in K-115 at 1 or 10 μM, Y-27632 at 10 μM, or fasudil at 10 μM for 60 min. PBS is used as a control vehicle. Drug solutions are removed and replaced with DMEM containing 10% FBS after 2 h. Cells are fixed with 4% paraformaldehyde in PBS for 15 min then washed with cytoskeletal buffer (10 mM MES, 150 mM NaCl, 5 mM EGTA, 5 mM MgCl2, 5 mM glucose, pH 6.1) and serum buffer (10% FBS in PBS). Cells are permeabilized with 0.5% Triton X-100 in PBS for 12 min at room temperature and blocked with serum buffer for at least 2 h at 4°C. Filamentous actin (F-actin) is labeled with 0.05 mg/mL Phalloidin-TRITC for 1 h at room temperature. After washing with PBS, cells are mounted with commercial mounting medium containing DAPI and observed using a fluorescence microscope. The exposure to take images for F-actin and DAPI are 0.1 and 0.05 sec, respectively[2].

Animal Administration [1]
Rabbits[1] In the rabbit experiments, 50 mL of vehicle or K-115 at concentrations of 0.0625%, 0.125%, 0.25, or 0.5% is instilled into one eye. Intraocular pressure (IOP) is measured in both eyes before and 0.5, 1, 2, 3, 4, and 5 h after instillation. The contralateral eye is not treated. Animals are administered all concentrations of K-115 assigned using the Latin square method with intervals of at least 2 d. Monkeys[1] In the monkey experiments, 20 mL of K-115 at concentrations of 0.1%, 0.2%, or 0.4%, and latanoprost at a concentration of 0.005% are instilled into one eye. IOP is measured in both eyes before and 1, 2, 4, 6, and 8 h after instillation. The contralateral eye is not treated. Animals are arranged to receive all formulations with intervals of at least 1 week using the Latin square method. The IOPs are compared with the results for the instillation side at pre-dose and at each time point after instillation of K-115, and are compared with both eyes at each time point.

References:
[1]. Isobe T, et al. Effects of K-115, a rho-kinase inhibitor, on aqueous humor dynamics in rabbits. Curr Eye Res. 2014 Aug;39(8):813-22. [2]. Kaneko Y, et al. 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]. Yamamoto K, et al. 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.

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Preparing Stock Solutions of K-115

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.526 mL 12.6301 mL 25.2602 mL 50.5204 mL 63.1504 mL
5 mM 0.5052 mL 2.526 mL 5.052 mL 10.1041 mL 12.6301 mL
10 mM 0.2526 mL 1.263 mL 2.526 mL 5.052 mL 6.315 mL
50 mM 0.0505 mL 0.2526 mL 0.5052 mL 1.0104 mL 1.263 mL
100 mM 0.0253 mL 0.1263 mL 0.2526 mL 0.5052 mL 0.6315 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on K-115

Ripasudil (K-115) is a novel Rho kinase inhibitor with a potent intraocular pressure-lowering effect. Rho-kinase can be activated by the small GTP-binding protein Rho. Growing evidence has demonstrated that Rho/Rho-kinase pathway has been implicated in various cellular functions, such as vascular smooth muscle cell (VSMC) contraction, actin cytoskeleton organization, cell adhesion and motility, cytokinesis, and gene expressions. Dysfunctions of these may be involved in the pathogenesis of cardiovascular disease such as coronary artery spasm [1].

In vivo: In an optic nerve crush (NC) C57BL/6 mice model, oral administration of K-115 (1 mg/kg/d) increased 34 ± 3% survival of RGCs after NC [2].

Clinical Trials: In the phase 1 clinical trials, when tested in 2 hours after instillation, the intraocular pressure (IOP) of healthy male adult volunteers increased from -1.6 mm Hg for placebo to -3.4, -2.2, -2.6, -4.0, and -4.3 mm Hg in concentrations of 0.05%, 0.1%, 0.2%, 0.4%, and 0.8%, respectively [3]. In the phase 2 randomized clinical study, treatment with K-115 twice daily for 8 weeks in patients with primary open-angle glaucoma or ocular hypertension dose-dependently lowered the IOP level [4].

References:
Shimokawa H, Takeshita A.  Rho-kinase is an important therapeutic target in cardiovascular medicine[J]. Arteriosclerosis, thrombosis, and vascular biology, 2005, 25(9): 1767-1775.
Yamamoto K, Maruyama K, Himori N, et al.  The Novel Rho Kinase (ROCK) Inhibitor K-115: A New Candidate Drug for Neuroprotective Treatment in GlaucomaNovel Rho Kinase Inhibitor[J]. Investigative ophthalmology & visual science, 2014, 55(11): 7126-7136.
Tanihara H, Inoue T, Yamamoto T, et al.  Phase 1 clinical trials of a selective Rho kinase inhibitor, K-115[J]. JAMA ophthalmology, 2013, 131(10): 1288-1295.
Tanihara H, Inoue T, Yamamoto T, et al.  Phase 2 randomized clinical study of a Rho kinase inhibitor, K-115, in primary open-angle glaucoma and ocular hypertension[J]. American journal of ophthalmology, 2013, 156(4): 731-736. e2.

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References on K-115

Vascular Normalization by ROCK Inhibitor: Therapeutic Potential of Ripasudil (K-115) Eye Drop in Retinal Angiogenesis and Hypoxia.[Pubmed:27124322]

Invest Ophthalmol Vis Sci. 2016 Apr 1;57(4):2264-76.

PURPOSE: In this study, we investigated the therapeutic potential of a Rho-associated coiled-coil-containing protein kinase (ROCK) inhibitor ripasudil (K-115) eye drop on retinal neovascularization and hypoxia. METHODS: In vitro, human retinal microvascular endothelial cells (HRMECs) were pretreated with ripasudil and then stimulated with VEGF. ROCK activity was evaluated by phosphorylation of myosin phosphatase target protein (MYPT)-1. Endothelial migration and cell viability were assessed by cell migration and MTT assay, respectively. The concentration of ripasudil in the retina was measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). In vivo, normal saline, 0.4%, or 0.8% ripasudil were administered three times a day to mice with oxygen-induced retinopathy (OIR). The areas of neovascularization and avascular retina were also quantified with retinal flat-mounts at postnatal day (P) 15, P17, or P21. The retinal hypoxic area was evaluated using hypoxia-sensitive drug pimonidazole by immunohistochemistry at P17. The vascular normalization was also evaluated by immunohistochemistry at P17. RESULTS: Ripasudil but not fasudil significantly reduced VEGF-induced MYPT-1 phosphorylation in HRMECs at 30 mumol/L. Ripasudil significantly inhibited VEGF-induced HRMECs migration and proliferation. The concentration of ripasudil in the retina was 3.8 to 10.4 mumol/L and 6.8 to 14.8 mumol/L after 0.4% and 0.8% ripasudil treatment, respectively. In the 0.4% and 0.8% ripasudil treated OIR mice, the areas of neovascularization as well as avascular area in the retina was significantly reduced compared with those of saline-treated mice at P17 and P21. Pimonidazole staining revealed that treatment with 0.4% and 0.8% ripasudil significantly inhibited the increase in the hypoxic area compared with saline. 0.8% ripasudil could cause intraretinal vascular sprouting and increase retinal vascular perfusion. CONCLUSIONS: Novel ROCK inhibitor ripasudil eye drop has therapeutic potential in the treatment of retinal hypoxic neovascular diseases via antiangiogenic effects as well as vascular normalization.

The effects of ripasudil (K-115), a Rho kinase inhibitor, on activation of human conjunctival fibroblasts.[Pubmed:27394186]

Exp Eye Res. 2016 Aug;149:107-115.

The most common cause of glaucoma surgery failure is scar formation induced by activation of wound-healing responses and resultant fibrosis at the surgical site. We investigated the effects of ripasudil, a Rho kinase inhibitor, on activation of human conjunctival fibroblasts (HConF). HConF were pretreated with different concentrations of ripasudil for 1 h before addition of transforming growth factor (TGF)-beta2, followed by incubation for 48 h. TGF-beta2-treated fibroblasts exhibited a significant increase in expression of alpha-smooth muscle actin (alpha-SMA), a marker of fibroblast-to-myofibroblast differentiation, and this increase was significantly suppressed, in a dose-dependent manner, by pretreatment with ripasudil. Ripasudil pretreatment also significantly attenuated TGF-beta2-induced fibronectin production and collagen gel contraction. TGF-beta2 increased both the number of viable cells and the number of cells in the G2/M phase of the cell cycle; these effects were attenuated by pretreatment with ripasudil. In addition, we explored the effects of ripasudil on stimulation of HConF by activated macrophages. Human monocytic cell line THP-1 cells were differentiated into M1 or M2 macrophage-like cells, and HConF were treated with conditioned media derived from these macrophages in the presence or absence of ripasudil. Conditioned medium from M2 macrophage-like cells induced a significant increase in alpha-SMA expression, viable cell numbers, and gel contraction, all of which were significantly suppressed by ripasudil. Thus, overall, ripasudil attenuated activation of human conjunctival fibroblasts. Ripasudil may be of therapeutic utility, preventing excessive scarring after glaucoma filtration surgery.

Species differences in metabolism of ripasudil (K-115) are attributed to aldehyde oxidase.[Pubmed:26678038]

Xenobiotica. 2016 Jul;46(7):579-590.

1. We examined the metabolism of ripasudil (K-115), a selective and potent Rho-associated coiled coil-containing protein kinase (ROCK) inhibitor, by in vitro and in vivo studies. 2. First, we identified metabolites and metabolic enzymes involved in ripasudil metabolism. Species differences were observed in metabolic clearance and profiles of metabolites in liver S9 fraction and hepatocytes. In addition, ripasudil was metabolised in humans and monkey S9 without nicotinamide adenine dinucleotide phosphate (NADPH). Studies using specific inhibitors and human recombinant enzyme systems showed that M1 (main metabolite in humans) formation is mediated by aldehyde oxidase (AO). 3. Therefore, we developed ripasudil as an ophthalmic agent. First, we compared the pharmacokinetic profiles of ripasudil in humans and rats. The results indicated rapid disappearance of ripasudil from the circulation after instillation in humans and its level remained relatively high only in M1. In contrast, we found six metabolites from M1 to M6 in plasma after oral administration to rats. 4. Analysis of enzyme kinetics using S9 showed that the formation of M1 is the major metabolic pathway of ripasudil in humans even though CYP3A4/3A5 and CYP2C8/3A4/3A5 were associated with the formation of M2 and M4, respectively. In conclusion, AO causes differences in ripasudil metabolism between species.

Effects of K-115 (Ripasudil), a novel ROCK inhibitor, on trabecular meshwork and Schlemm's canal endothelial cells.[Pubmed:26782355]

Sci Rep. 2016 Jan 19;6:19640.

Ripasudil hydrochloride hydrate (K-115), a specific Rho-associated coiled-coil containing protein kinase (ROCK) inhibitor, was the first ophthalmic solution developed for the treatment of glaucoma and ocular hypertension in Japan. Topical administration of K-115 decreased intraocular pressure (IOP) and increased outflow facility in rabbits. This study evaluated the effect of K-115 on monkey trabecular meshwork (TM) cells and Schlemm's canal endothelial (SCE) cells. K-115 induced retraction and rounding of cell bodies as well as disruption of actin bundles in TM cells. In SCE-cell monolayer permeability studies, K-115 significantly decreased transendothelial electrical resistance (TEER) and increased the transendothelial flux of FITC-dextran. Further, K-115 disrupted cellular localization of ZO-1 expression in SCE-cell monolayers. These results indicate that K-115 decreases IOP by increasing outflow facility in association with the modulation of TM cell behavior and SCE cell permeability in association with disruption of tight junction.

Description

Ripasudil (K-115) is a specific inhibitor of ROCK, with IC50s of 19 and 51 nM for ROCK2 and ROCK1, respectively.

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