Nafamostat mesylate CAS#: 82956-11-4; ChemWhat Code: 83931

IdentificationPhysical DataSpectra
Route of Synthesis (ROS)Safety and HazardsOther Data

Identification

Product NameNafamostat mesylate
IUPAC Name(6-carbamimidoylnaphthalen-2-yl) 4-(diaminomethylideneamino)benzoate;methanesulfonic acid
Molecular StructureStructure of Nafamostat mesylate CAS 82956-11-4
CAS Registry Number 82956-11-4
MDL NumberMFCD00941430
Synonymsnafamostat 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 FormulaC21H25N5O8S2
Molecular Weight539.582
InChIInChI=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 KeySRXKIZXIRHMPFW-UHFFFAOYSA-N
Canonical SMILESCS(=O)(=O)O.CS(=O)(=O)O.c1cc(ccc1C(=O)Oc2ccc3cc(ccc3c2)C(=N)N)NC(=N)N
Patent Information
Patent IDTitlePublication 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

AppearanceWhite powder
SolubilityNo data available
Flash PointNo data available
Refractive indexNo data available
SensitivityNo 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 shifts1Hdimethylsulfoxide-d6
Description (IR Spectroscopy)Solvent (IR Spectroscopy)Comment (IR Spectroscopy)
BandsKBr 3500 – 1679 cm**(-1)

Route of Synthesis (ROS)

Route of Synthesis (ROS) of Nafamostat mesylate CAS 82956-11-4
Route of Synthesis (ROS) of Nafamostat mesylate CAS 82956-11-4
ConditionsYield
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)health-hazard
SignalWarning
GHS Hazard StatementsH361 (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 CodesP201, P202, P281, P308+P313, P405, and P501
(The corresponding statement to each P-code can be found at the GHS Classification page.)

Other Data

TransportationNONH for all modes of transport
Under the room temperature and away from light
HS Code292529
StorageUnder the room temperature and away from light
Shelf Life1 year
Market PriceUSD
Druglikeness
Lipinski rules component
Molecular Weight539.59
HBA9
HBD6
Matching Lipinski Rules2
Veber rules component
Polar Surface Area (PSA)200.82
Rotatable Bond (RotB)6
Matching Veber Rules1
Bioactivity
In vitro: Efficacy
Quantitative Results
pXParameterValue (qual)Value (quant)UnitTargetDose Concomitants
10IC50=1E-10 M Trypsin-1:Wildantiviral agentSubstrate: H-D-Phe-Arg-CHA.2HCl
10Ki (inhibition constant)=95pMBeta-tryptase [human]:Wild
9.68 IC50 0.21 nM Suppressor of tumorigenicity 14 protein [human]:Wild0.0038 – 9.6 nM
8.48 IC50 0.0033 µMKallikrein-8 [human]:Wild
7.7 IC502E-08MPlasmin:Wild
6.54 IC50=2.9E-07MPlasminogen:Wild
5.52Kd (dissociation constant)~3 – 3.26 μM Alpha-ketoglutarate-dependent dioxygenase FTO:Wild
5 inhibition rate(apical tryptic activity)ActiveHigh voltage-activated calcium channel [rat]:Wild10 μM
Quantitative Results
1 of 10Assay 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 10Target 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 10Biological 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 DescriptionEffect : 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 DescriptionEffect : 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
Resultstitle 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 10Assay 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 DescriptionEffect : 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
Resultstitle 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
pXParameterValue (qual)Animal Model Dose Effect
1percentage decrease Not active experimental liver metastasis 30 mg/kg
1inhibition rate(Visceromotor responses) Not activetrinitrobenzene sulfonic acid-induced colitis 10 mg/kg
TGI (tumor growth inhibition rate) Not activeXenograft 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 decreaseActive experimental liver metastasis 30 mg/kg antimetastatic agent
percentage decreaseActive experimental liver metastasis 10 mg/kg antimetastatic agent
Metabolism
Quantitative Results
pX ParameterValue (qual) Value (quant) Unit Target Dose
6.3IC50 ~0.5µM Solute carrier family 22 member 2 [rat]:Wild0.0500000 µM
4.3IC50 ~50µM Solute carrier family 22 member 1 [rat]:Wild0.0500000 µM
3.3inhibition rate Active Solute carrier family 22 member 5 [human]:Wild 500 µM
2.05Km (Michaelis constant) 8890 µM A-esterase [human]:Wild 25 µM
half life time(ALL) 18.8 minute A-esterase [human]:Wild100µM
Rate 0.0521 – 0.187 nmol/min/mg protein Carboxylesterase 2 [human]:Wild10µM
CLint (intrinsic clearance) 443µL/min/mL tissue A-esterase [human]:Wild60µM
Vmax 278 nmol/min/mL tissue A-esterase [human]:Wild60µM
CLint (intrinsic clearance)15µL/min/mg protein Carboxylesterase 2 [human]:Wild10 µM
Toxicity/Safety pharmacology
Quantitative Results
pX Parameter Value (qual) Value (quant) Unit Dose Effect
9.95concentration (parameter)(IL-8 Release) 61pg/mL 200 µM
8.69 concentration (parameter)(IL-8 Release) 1096pg/mL 30µM
5.26percentage decrease(Colony formation) ~90%50µM antineoplastic agent
4.6percentage decrease(Colony formation) Active 25µM antineoplastic agent
4.3MIC 50µM
3.7inhibition rate Active 200µM antineoplastic agent
3.52inhibition rate Active <= 300 μM antineoplastic agent
3.3MIC 500 µM
1percentage 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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