Nafamostat mesylate CAS#: 82956-11-4; ChemWhat Code: 83931
Identification
Product Name | Nafamostat mesylate |
IUPAC Name | (6-carbamimidoylnaphthalen-2-yl) 4-(diaminomethylideneamino)benzoate;methanesulfonic acid |
Molecular Structure | |
CAS Registry Number | 82956-11-4 |
MDL Number | MFCD00941430 |
Synonyms | nafamostat mesylate, Nafamostat mesylate, FUT 175, nafamostat mesilate, tryptase inhibitor NM, 6′-amidino-2′-naphthyl-4-guanidinobenzoate dimethanesulfonate, 6-amidino-2-naphthyl p-guanidino-benzoate dimethanesulfonate CAS: 82956-11-4 CAS No:82956-11-4 |
Molecular Formula | C21H25N5O8S2 |
Molecular Weight | 539.582 |
InChI | InChI=1S/C19H17N5O2.2CH4O3S/c20-17(21)14-2-1-13-10-16(8-5-12(13)9-14)26-18(25)11-3-6-15(7-4-11)24-19(22)23;21-5(2,3)4/h1-10H,(H3,20,21)(H4,22,23,24);21H3,(H,2,3,4) |
InChI Key | SRXKIZXIRHMPFW-UHFFFAOYSA-N |
Canonical SMILES | CS(=O)(=O)O.CS(=O)(=O)O.c1cc(ccc1C(=O)Oc2ccc3cc(ccc3c2)C(=N)N)NC(=N)N |
Patent Information | ||
Patent ID | Title | Publication Date |
US2009/88472 | Protective Agent for Neuronal Cell Comprising Amidino Derivative as Active Ingredient | 2009 |
EP1884237 | PROTECTIVE AGENT FOR NEUROCYTE COMPRISING AMIDINO DERIVATIVE AS ACTIVE INGREDIENT | 2008 |
EP1884236 | ANGIOGENESIS INHIBITOR CONTAINING AMINE DERIVATIVE AS ACTIVE INGREDIENT | 2008 |
US6534283 | Method for treatment and prevention of physiological shock | 2003 |
US2003/190368 | METHODS OF DIAGNOSIS AND TRIAGE USING CELL ACTIVATION MEASURES | 2003 |
Physical Data
Appearance | White powder |
Solubility | No data available |
Flash Point | No data available |
Refractive index | No data available |
Sensitivity | No data available |
Melting Point, °C | Solvent (Melting Point) | Comment (Melting Point) |
260 | H2O | Decomposition |
Spectra
Description (NMR Spectroscopy) | Nucleus (NMR Spectroscopy) | Solvents (NMR Spectroscopy) |
Chemical shifts | 1H | dimethylsulfoxide-d6 |
Description (IR Spectroscopy) | Solvent (IR Spectroscopy) | Comment (IR Spectroscopy) |
Bands | KBr | 3500 – 1679 cm**(-1) |
Route of Synthesis (ROS)
Conditions | Yield |
In methanol at 15 – 20℃; for 0.166667h; Experimental Procedure 1 Preparation of nafamostat mesilate At room temperature25.94 g of 4-guanidinobenzoic acid hydrochloride (4-GDA.HCl) was added to 207.5 ml of pyridine solvent, 18.6 ml of N, N’-diisopropylcarbodiimide (DIC) was added and reacted. to the next, to the reaction solution comprising the above reaction, 28.3 g of 6-amidino-2-naphthol methanesulfonate (6-ANL.MsOH) and 122 mg of 4-dimethylaminopyridine (DMAP) The mixture was stirred overnight at the same temperature as that of the reaction. next, methanol (MeOH) (69.3 ml) was added to the reaction mixture which had been stirred, stirred for 1 hour, filtered, Subsequently, the compound of Formula 1 purified by a purity of 99% by a further purification process, in that not dry, saturated sodium in 233.28 ml of water (H2O) and 92.73 ml for 1 hour at a temperature of 25 ° C bicarbonate (NaHCO3) is added slowly to a mixed solution (solvent), and the crystal precipitates and stirred, after it was filtered, using a water and acetone by washing sequentially, the compound (purity according to the general formula (2): 98.9% ) was prepared. To the next, the compound of formula (2) Without drying, after the mixture was dispersed in 72.87 ml of methanol while maintaining the temperature at room temperature,9.3 ml of methanesulfonic acid (MsOH) was slowly added, The mixture was continuously stirred until no gas was generated. Then, it was cooled to 15 DEG C, After stirring for 10 minutes at the same temperature, the resulting solid was filtered,Washed sequentially with methanol and acetone, By hot air drying at a temperature of 50°C, by drying (Purity: 99.1%, yield: 62.78%) of the nafamostat mesilate according to the above formula (3). | 62.78% |
Safety and Hazards
Pictogram(s) | |
Signal | Warning |
GHS Hazard Statements | H361 (100%): Suspected of damaging fertility or the unborn child [Warning Reproductive toxicity] [Warning Hazardous to the aquatic environment, long-term hazard] Information may vary between notifications depending on impurities, additives, and other factors. |
Precautionary Statement Codes | P201, P202, P281, P308+P313, P405, and P501 (The corresponding statement to each P-code can be found at the GHS Classification page.) |
Other Data
Transportation | NONH for all modes of transport |
Under the room temperature and away from light | |
HS Code | 292529 |
Storage | Under the room temperature and away from light |
Shelf Life | 1 year |
Market Price | USD |
Druglikeness | |
Lipinski rules component | |
Molecular Weight | 539.59 |
HBA | 9 |
HBD | 6 |
Matching Lipinski Rules | 2 |
Veber rules component | |
Polar Surface Area (PSA) | 200.82 |
Rotatable Bond (RotB) | 6 |
Matching Veber Rules | 1 |
Bioactivity |
In vitro: Efficacy |
Quantitative Results |
pX | Parameter | Value (qual) | Value (quant) | Unit | Target | Dose | Concomitants |
10 | IC50 | = | 1E-10 | M | Trypsin-1:Wild | antiviral agent | Substrate: H-D-Phe-Arg-CHA.2HCl |
10 | Ki (inhibition constant) | = | 95 | pM | Beta-tryptase [human]:Wild | ||
9.68 | IC50 | 0.21 | nM | Suppressor of tumorigenicity 14 protein [human]:Wild | 0.0038 – 9.6 nM | ||
8.48 | IC50 | 0.0033 | µM | Kallikrein-8 [human]:Wild | |||
7.7 | IC50 | 2E-08 | M | Plasmin:Wild | |||
6.54 | IC50 | = | 2.9E-07 | M | Plasminogen:Wild | ||
5.52 | Kd (dissociation constant) | ~ | 3 – 3.26 | μM | Alpha-ketoglutarate-dependent dioxygenase FTO:Wild | ||
5 | inhibition rate(apical tryptic activity) | Active | High voltage-activated calcium channel [rat]:Wild | 10 μM |
Quantitative Results | ||
1 of 10 | Assay Description | Effect : choroidal neovascularization; inhibition of Target : with laser-induced choroidal neovascularization of rat Bioassay : [Pharmacological Test] In order to study the inhibitory effect of a compound represented by the general formula [I] or a salt thereof on angiogenesis, the effects of nafamostat, FUT-187 and camostat, which are compounds represented by the general formula [I] or salts thereof, on laser-induced choroidal |
Results | intravitreal treatment with title compound at 10 nmol/eye inhibited choroidal neovascularization with an inhibition rate of 26.5% after 7 days | |
2 of 10 | Biological material | rat |
Assay Description | Effect : choroidal neovascularization; inhibition of Bioassay : with laser-induced choroidal neovascularization [Pharmacological Test] In order to study the inhibitory effect of a compound represented by the general formula [I] or a salt thereof on angiogenesis, the effects of nafamostat, FUT-187 and camostat, which are compounds represented by the general formula [I] or salts thereof, on laser-induced choroidal | |
Results | subconjunctival treatment with title compound at 100 μg/eye/day inhibited choroidal neovascularization with an inhibition rate of 51.6% after 7 days | |
3 of 10 | Target | Tryptase beta-2 [mouse]:Wild |
Biological material | mouse | |
Assay Description | Binding activity of the compound towards mouse Mast cell protease 6 (MCPT-6) | |
4 of 10 | Biological material | human erythrocyte |
Assay Description | Effect : effect on potassium transport in erythrocytes Bioassay : effect of title comp. on potassium transport in erythrocytes in vitro; cells were incubated for 60 min at 37 degC, washed, haemolysed with distil. H2O; radioactivity was counted blood cells from 8 healthy subj.; potassium influx measured using 86RbCl (spec. activ. 100 μCi); 10 μl of 86RbCl diluted in 1 ml H2O, 10 μl of this solution added to 220 μl aliquots of erythrocyte suspension; title comp. added to give various. conc. | |
Results | basal Rb uptake was 28.2 nmol.1E-(-9) cells/h; Rb uptake unaffected by title comp. in conc. of 1E-(-6) and 1E-(-5) mol/l, but at 1E-(-4) mol/l title comp. inhibited Rb uptake by 18.4(2.68) percent, at 1E-(-3) mol/l it further inhib. it by 44.6(7.48) | |
5 of 10 | Biological material | human erythrocyte |
Assay Description | Effect : drug interaction Bioassay : effect of various drugs on inhibitory action of title comp. on potassium influx; specific inhibitors (10 μl) added to erythrocytes; cells were incubated for 60 min at 37 degC, washed, haemolysed with distil. H2O; radioactivity was counted blood cells from 8 healthy subj.; potassium influx measured using 86RbCl (spec. activ. 100 μCi); 10 μl of 86RbCl diluted in 1 ml H2O, 10 μl of this solution added to 220 μl aliquots of erythrocyte suspension; title comp. added to give various. conc. | |
Results | neither amiloride, BaCl2 nor frusemide affected inhibitory action of title comp. on Rb uptake (and potassium influx); ouabain supressed Rb uptake by 63.9 (1.4) percent and in the presence of ouabain the inhibitory effect of title comp. was signific. | |
6 of 10 | Biological material | human |
Assay Description | Effect : alternative pathway-dependent amplification of C3b cleavage; inhibition of Bioassay : Bruch’s membrane with age-related macular degeneration (AMD) EXAMPLE 1Suppression Of Complement Activation On RPE Cells By FUT-175[0041] To determine how effective FUT-175 is in preventing alternative pathway-dependent amplification of complement activation on Bruch’s membrane and RPE cells, we seeded purified Bruch’s membrane from an AMD patient and the RPE-43 | |
Results | title compound treatment inhibited further C3b activation in a dose-dependent manner; ~50% inhibition was achieved in both sites at 0.3µM; figure is given | |
7 of 10 | Assay Description | Effect : alternative pathway-dependent amplification of C3b cleavage; inhibition of Bioassay : RPE-43 cells EXAMPLE 1Suppression Of Complement Activation On RPE Cells By FUT-175[0041] To determine how effective FUT-175 is in preventing alternative pathway-dependent amplification of complement activation on Bruch’s membrane and RPE cells, we seeded purified Bruch’s membrane from an AMD patient and the RPE-43 |
Results | title compound treatment inhibited further C3b activation in a dose-dependent manner; ~50% inhibition was achieved in both sites at 0.3µM; figure is given | |
8 of 10 | Assay Description | Effect : alternative pathway-dependent amplification of C3b cleavage; inhibition of EXAMPLE 1Suppression Of Complement Activation On RPE Cells By FUT-175[0041] To determine how effective FUT-175 is in preventing alternative pathway-dependent amplification of complement activation on Bruch’s membrane and RPE cells, we seeded purified Bruch’s membrane from an AMD patient and the RPE-43 |
Results | title compound treatment inhibited further C3b activation in a dose-dependent manner; ~50% inhibition was achieved in both sites at 0.3µM; figure is given | |
9 of 10 | Assay Description | Effect : alternative pathway-dependent amplification of C3b cleavage; inhibition of Bioassay : EXAMPLE 1Suppression Of Complement Activation On RPE Cells By FUT-175[0041] To determine how effective FUT-175 is in preventing alternative pathway-dependent amplification of complement activation on Bruch’s membrane and RPE cells, we seeded purified Bruch’s membrane from an AMD patient and the RPE-43 |
Results | title compound treatment inhibited further C3b activation in a dose-dependent manner; ~50% inhibition was achieved in both sites at 0.3µM; figure is given | |
10 of 10 | Assay Description | Effect : alternative pathway-dependent amplification of C3b cleavage; inhibition of Target : Bruch’s membrane with age-related macular degeneration (AMD) of human Bioassay : EXAMPLE 1Suppression Of Complement Activation On RPE Cells By FUT-175[0041] To determine how effective FUT-175 is in preventing alternative pathway-dependent amplification of complement activation on Bruch’s membrane and RPE cells, we seeded purified Bruch’s membrane from an AMD patient and the RPE-43 |
Results | title compound treatment inhibited further C3b activation in a dose-dependent manner; ~50% inhibition was achieved in both sites at 0.3µM; figure is given |
In vivo: Animal Model |
Quantitative Results |
pX | Parameter | Value (qual) | Animal Model | Dose | Effect |
1 | percentage decrease | Not active | experimental liver metastasis | 30 mg/kg | |
1 | inhibition rate(Visceromotor responses) | Not active | trinitrobenzene sulfonic acid-induced colitis | 10 mg/kg | |
TGI (tumor growth inhibition rate) | Not active | Xenograft model | 30 mg/kg | antimetastatic agent | |
tumor weight decrease(Tumor weight) | Active | Xenograft model | 30 mg/kg | antimetastatic agent | |
percentage decrease(metastatic nodules) | Active | experimental liver metastasis | 30 mg/kg | antimetastatic agent | |
percentage decrease(metastatic nodules) | Active | experimental liver metastasis | 10 mg/kg | antimetastatic agent | |
percentage decrease | Active | experimental liver metastasis | 30 mg/kg | antimetastatic agent | |
percentage decrease | Active | experimental liver metastasis | 10 mg/kg | antimetastatic agent |
Metabolism |
Quantitative Results |
pX | Parameter | Value (qual) | Value (quant) | Unit | Target | Dose |
6.3 | IC50 | ~ | 0.5 | µM | Solute carrier family 22 member 2 [rat]:Wild | 0.0500000 µM |
4.3 | IC50 | ~ | 50 | µM | Solute carrier family 22 member 1 [rat]:Wild | 0.0500000 µM |
3.3 | inhibition rate | Active | Solute carrier family 22 member 5 [human]:Wild | 500 µM | ||
2.05 | Km (Michaelis constant) | 8890 | µM | A-esterase [human]:Wild | 25 µM | |
half life time(ALL) | 18.8 | minute | A-esterase [human]:Wild | 100µM | ||
Rate | 0.0521 – 0.187 | nmol/min/mg protein | Carboxylesterase 2 [human]:Wild | 10µM | ||
CLint (intrinsic clearance) | 443 | µL/min/mL tissue | A-esterase [human]:Wild | 60µM | ||
Vmax | 278 | nmol/min/mL tissue | A-esterase [human]:Wild | 60µM | ||
CLint (intrinsic clearance) | 15 | µL/min/mg protein | Carboxylesterase 2 [human]:Wild | 10 µM |
Toxicity/Safety pharmacology |
Quantitative Results |
pX | Parameter | Value (qual) | Value (quant) | Unit | Dose | Effect |
9.95 | concentration (parameter)(IL-8 Release) | 61 | pg/mL | 200 µM | ||
8.69 | concentration (parameter)(IL-8 Release) | 1096 | pg/mL | 30µM | ||
5.26 | percentage decrease(Colony formation) | ~ | 90 | % | 50µM | antineoplastic agent |
4.6 | percentage decrease(Colony formation) | Active | 25µM | antineoplastic agent | ||
4.3 | MIC | 50 | µM | |||
3.7 | inhibition rate | Active | 200µM | antineoplastic agent | ||
3.52 | inhibition rate | Active | <= 300 μM | antineoplastic agent | ||
3.3 | MIC | 500 | µM | |||
1 | percentage decrease | Not active | 30mg/kg |
Use Pattern |
Nafamostat mesylate CAS#: 82956-11-4 can Protective agent for a neuronal cell |
Nafamostat mesylate CAS#: 82956-11-4 – Disorders associated with complement activation |
T cell autoreactivity in autoimmune disease associated with complement activation |
Nafamostat mesylate CAS#: 82956-11-4 as Retinal disease |
graft versus host disease |
T-cell mediated pulmonary diseases |
Nafamostat mesylate CAS#: 82956-11-4 as pulmonary fibrosis |
Hashimoto’s thyroiditis |
systemic lupus erythematosis |
Nafamostat mesylate CAS#: 82956-11-4 can Retinal disease that is associated with intraoccular complement activation |
Nafamostat mesylate CAS#: 82956-11-4 Choroidal degenerative disease that is associated with intraoccular complement activation |
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