Identification

Name
Nafamostat
Accession Number
DB12598
Type
Small Molecule
Groups
Investigational
Description

Nafamostat is a synthetic serine protease inhibitor that is commonly formulated with hydrochloric acid due to its basic properties. It has been used in trials studying the prevention of Liver Transplantation and Postreperfusion Syndrome. The use of nafamostat in Asian countries is approved as an anticoagulant therapy for patients undergoing continuous renal replacement therapy due to acute kidney injury.

Structure
Thumb
Synonyms
  • FUT-175
  • Nafamostat dimethanesulfonate
  • Nafamostat mesilate
Product Ingredients
IngredientUNIICASInChI Key
Nafamostat mesylate1D2T74921W82956-11-4ZESSXQLDESEKGC-UHFFFAOYSA-N
International/Other Brands
Berabu (Tobishi Pharmaceutical, Japan) / Buipel (Teva Seiyaku, Japan) / Buseron (Sawai Seiyaku, Japan) / Coahibitor (AY Pharma, Japan) / Famoset (Towa Yakuhin, Japan) / Futhan (Torii Yakuhin, Japan) / Nafaston (Fuji Seiyaku, Japan) / Nafatat (Nichi-Iko Pharmaceutical, Japan) / Namostatt (Pola Pharma, Japan) / Naotamin (Asahi Kasei Pharma, Japan) / Opsun (Sanwa Kagaku, Japan) / Pathron (Nipro, Japan) / Ronastat (Koa Isei, Japan)
Categories
UNII
Y25LQ0H97D
CAS number
81525-10-2
Weight
Average: 347.378
Monoisotopic: 347.138224807
Chemical Formula
C19H17N5O2
InChI Key
MQQNFDZXWVTQEH-UHFFFAOYSA-N
InChI
InChI=1S/C19H17N5O2/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/h1-10H,(H3,20,21)(H4,22,23,24)
IUPAC Name
6-carbamimidoylnaphthalen-2-yl 4-carbamimidamidobenzoate
SMILES
NC(=N)NC1=CC=C(C=C1)C(=O)OC1=CC=C2C=C(C=CC2=C1)C(N)=N

Pharmacology

Indication

Used as an anticoagulant in patients with disseminative blood vessel coagulation, hemorrhagic lesions, and hemorrhagic tendencies. It prevents blood clot formation during extracorporeal circulation in patients undergoing continuous renal replacement therapy and extra corporeal membrane oxygenation.

Pharmacodynamics

Nafamostat is a fast-acting proteolytic inhibitor used during hemodialysis to prevent the proteolysis of fibrinogen into fibrin by competitively inhibiting several serine proteases including thrombin. It improves acute pancreatitis and prevents blood clot formation during extracorporeal circulation and has an anti-inflammatory effect in vitro. A study suggets that nafamostat has a neuroprotective role during ischemia-induced brain injury from antithrombin activity [5].

Mechanism of action

Nafamostat mesilate inhibits various enzyme systems, such as coagulation and fibrinolytic systems (thrombin, Xa, and XIIa), the kallikrein–kinin system, the complement system, pancreatic proteases and activation of protease-activated receptors (PARs) [6]. Nafamostat inhibits lipopolysaccharide-induced nitric oxide production, apoptosis, and interleukin (IL)-6 and IL-8 levels in cultured human trophoblasts. It is shown to act as an antioxidant in TNF-α-induced ROS production [2].

TargetActionsOrganism
AProthrombin
inhibitor
Human
ACoagulation factor X
inhibitor
Human
ACoagulation factor XII
inhibitor
Human
ATrypsin-1
inhibitor
Human
AKallikrein-1
inhibitor
Human
UIntercellular adhesion molecule 1
inhibitor
Human
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism

Nafamostat is mainly hydrolyzed by hepatic carboxyesterase and long-chain acyl-CoA hydrolase in human liver cytosol. Main metabolites are p-guanidinobenzoic acid (PGBA) and 6-amidino-2-naphthol (AN) as inactive protease inhibitors.

Route of elimination

Two metabolites of NM, p-guanidinobenzoic acid (PGBA) and 6-amidino-2-naphthol (AN), are renally excreted. Nafamostat accumulates in the kidneys.

Half life

Approximately 8 minutes [4]

Clearance
Not Available
Toxicity

Reported incidences of agranulocytosis, hyperkalemia, and anaphylaxis. The use of nafamostat has been reported to cause cardiac arrest in patients receiving dialysis due to a sudden change in the patient's condition such as dyspnea. A study suggests that the drug and its metabolites may inhibit the amiloride-sensitive sodium (Na) conductance at the collecting ducts, resulting in an inhibition of K secretion and hyperkalemia [7]. Reported LD50 value from intravenous administration in rats is 16.4mg/kg.

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(1,2,6,7-3H)TestosteroneThe therapeutic efficacy of Nafamostat can be increased when used in combination with (1,2,6,7-3H)Testosterone.
(R)-warfarinThe risk or severity of bleeding can be increased when Nafamostat is combined with (R)-warfarin.
(S)-WarfarinThe risk or severity of bleeding can be increased when Nafamostat is combined with (S)-Warfarin.
1-TestosteroneThe therapeutic efficacy of Nafamostat can be increased when used in combination with 1-Testosterone.
18-methyl-19-nortestosteroneThe therapeutic efficacy of Nafamostat can be increased when used in combination with 18-methyl-19-nortestosterone.
4-hydroxycoumarinThe risk or severity of bleeding can be increased when Nafamostat is combined with 4-hydroxycoumarin.
4-HydroxytestosteroneThe therapeutic efficacy of Nafamostat can be increased when used in combination with 4-Hydroxytestosterone.
5beta-dihydrotestosteroneThe therapeutic efficacy of Nafamostat can be increased when used in combination with 5beta-dihydrotestosterone.
AbciximabThe risk or severity of bleeding can be increased when Abciximab is combined with Nafamostat.
AceclofenacThe risk or severity of bleeding and hemorrhage can be increased when Aceclofenac is combined with Nafamostat.
Food Interactions
Not Available

References

General References
  1. Maruyama Y, Yoshida H, Uchino S, Yokoyama K, Yamamoto H, Takinami M, Hosoya T: Nafamostat mesilate as an anticoagulant during continuous veno-venous hemodialysis: a three-year retrospective cohort study. Int J Artif Organs. 2011 Jul;34(7):571-6. doi: 10.5301/IJAO.2011.8535. [PubMed:21786254]
  2. Kang MW, Song HJ, Kang SK, Kim Y, Jung SB, Jee S, Moon JY, Suh KS, Lee SD, Jeon BH, Kim CS: Nafamostat Mesilate Inhibits TNF-alpha-Induced Vascular Endothelial Cell Dysfunction by Inhibiting Reactive Oxygen Species Production. Korean J Physiol Pharmacol. 2015 May;19(3):229-34. doi: 10.4196/kjpp.2015.19.3.229. Epub 2015 Apr 30. [PubMed:25954127]
  3. Choi S, Kwon HJ, Song HJ, Choi SW, Nagar H, Piao S, Jung SB, Jeon BH, Kim DW, Kim CS: Nafamostat mesilate promotes endothelium-dependent vasorelaxation via the Akt-eNOS dependent pathway. Korean J Physiol Pharmacol. 2016 Sep;20(5):539-45. doi: 10.4196/kjpp.2016.20.5.539. Epub 2016 Aug 26. [PubMed:27610041]
  4. Choi JY, Kang YJ, Jang HM, Jung HY, Cho JH, Park SH, Kim YL, Kim CD: Nafamostat Mesilate as an Anticoagulant During Continuous Renal Replacement Therapy in Patients With High Bleeding Risk: A Randomized Clinical Trial. Medicine (Baltimore). 2015 Dec;94(52):e2392. doi: 10.1097/MD.0000000000002392. [PubMed:26717390]
  5. Chen T, Wang J, Li C, Zhang W, Zhang L, An L, Pang T, Shi X, Liao H: Nafamostat mesilate attenuates neuronal damage in a rat model of transient focal cerebral ischemia through thrombin inhibition. Sci Rep. 2014 Jul 2;4:5531. doi: 10.1038/srep05531. [PubMed:24985053]
  6. Kim HS, Lee KE, Oh JH, Jung CS, Choi D, Kim Y, Jeon JS, Han DC, Noh H: Cardiac arrest caused by nafamostat mesilate. Kidney Res Clin Pract. 2016 Sep;35(3):187-9. doi: 10.1016/j.krcp.2015.10.003. Epub 2015 Nov 12. [PubMed:27668164]
  7. Muto S, Imai M, Asano Y: Mechanisms of the hyperkalaemia caused by nafamostat mesilate: effects of its two metabolites on Na+ and K+ transport properties in the rabbit cortical collecting duct. Br J Pharmacol. 1994 Jan;111(1):173-8. [PubMed:8012693]
  8. FDA Executive Summary [Link]
External Links
PubChem Compound
4413
PubChem Substance
347828816
ChemSpider
4260
BindingDB
50063698
ChEBI
135466
ChEMBL
CHEMBL273264
Drugs.com
Drugs.com Drug Page
Wikipedia
Nafamostat
MSDS
Download (29.4 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedPreventionPostreperfusion Syndrome / Transplantation, Liver1
4CompletedTreatmentAcute Kidney Injury (AKI)2

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0341 mg/mLALOGPS
logP1.91ALOGPS
logP2.52ChemAxon
logS-4ALOGPS
pKa (Strongest Basic)11.32ChemAxon
Physiological Charge2ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count5ChemAxon
Polar Surface Area138.07 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity122.12 m3·mol-1ChemAxon
Polarizability37.5 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as guanidinobenzoic acids and derivatives. These are aromatic compounds containing a guanidine group linked to the benzene ring of a benzoic acid (or a derivative thereof).
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Benzoic acids and derivatives
Direct Parent
Guanidinobenzoic acids and derivatives
Alternative Parents
Naphthalenes / Benzoic acid esters / Benzoyl derivatives / Guanidines / Carboxylic acid esters / Propargyl-type 1,3-dipolar organic compounds / Monocarboxylic acids and derivatives / Carboximidamides / Carboxamidines / Organopnictogen compounds
show 3 more
Substituents
Guanidinobenzoic acid or derivatives / Benzoate ester / Naphthalene / Benzoyl / Carboxylic acid ester / Guanidine / Amidine / Carboxylic acid amidine / Carboxylic acid derivative / Monocarboxylic acid or derivatives
show 11 more
Molecular Framework
Aromatic homopolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Thrombospondin receptor activity
Specific Function
Thrombin, which cleaves bonds after Arg and Lys, converts fibrinogen to fibrin and activates factors V, VII, VIII, XIII, and, in complex with thrombomodulin, protein C. Functions in blood homeostas...
Gene Name
F2
Uniprot ID
P00734
Uniprot Name
Prothrombin
Molecular Weight
70036.295 Da
References
  1. Iwaki M, Ino Y, Motoyoshi A, Ozeki M, Sato T, Kurumi M, Aoyama T: Pharmacological studies of FUT-175, nafamostat mesilate. V. Effects on the pancreatic enzymes and experimental acute pancreatitis in rats. Jpn J Pharmacol. 1986 Jun;41(2):155-62. [PubMed:2427760]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Serine-type endopeptidase activity
Specific Function
Factor Xa is a vitamin K-dependent glycoprotein that converts prothrombin to thrombin in the presence of factor Va, calcium and phospholipid during blood clotting.
Gene Name
F10
Uniprot ID
P00742
Uniprot Name
Coagulation factor X
Molecular Weight
54731.255 Da
References
  1. Baek NN, Jang HR, Huh W, Kim YG, Kim DJ, Oh HY, Lee JE: The role of nafamostat mesylate in continuous renal replacement therapy among patients at high risk of bleeding. Ren Fail. 2012;34(3):279-85. doi: 10.3109/0886022X.2011.647293. Epub 2012 Jan 17. [PubMed:22251267]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Serine-type endopeptidase activity
Specific Function
Factor XII is a serum glycoprotein that participates in the initiation of blood coagulation, fibrinolysis, and the generation of bradykinin and angiotensin. Prekallikrein is cleaved by factor XII t...
Gene Name
F12
Uniprot ID
P00748
Uniprot Name
Coagulation factor XII
Molecular Weight
67791.53 Da
References
  1. Baek NN, Jang HR, Huh W, Kim YG, Kim DJ, Oh HY, Lee JE: The role of nafamostat mesylate in continuous renal replacement therapy among patients at high risk of bleeding. Ren Fail. 2012;34(3):279-85. doi: 10.3109/0886022X.2011.647293. Epub 2012 Jan 17. [PubMed:22251267]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Serine-type endopeptidase activity
Specific Function
Has activity against the synthetic substrates Boc-Phe-Ser-Arg-Mec, Boc-Leu-Thr-Arg-Mec, Boc-Gln-Ala-Arg-Mec and Boc-Val-Pro-Arg-Mec. The single-chain form is more active than the two-chain form aga...
Gene Name
PRSS1
Uniprot ID
P07477
Uniprot Name
Trypsin-1
Molecular Weight
26557.88 Da
References
  1. Ramjee MK, Henderson IM, McLoughlin SB, Padova A: The kinetic and structural characterization of the reaction of nafamostat with bovine pancreatic trypsin. Thromb Res. 2000 Jun 15;98(6):559-69. [PubMed:10899355]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Serine-type endopeptidase activity
Specific Function
Glandular kallikreins cleave Met-Lys and Arg-Ser bonds in kininogen to release Lys-bradykinin.
Gene Name
KLK1
Uniprot ID
P06870
Uniprot Name
Kallikrein-1
Molecular Weight
28889.425 Da
References
  1. Iwaki M, Ino Y, Motoyoshi A, Ozeki M, Sato T, Kurumi M, Aoyama T: Pharmacological studies of FUT-175, nafamostat mesilate. V. Effects on the pancreatic enzymes and experimental acute pancreatitis in rats. Jpn J Pharmacol. 1986 Jun;41(2):155-62. [PubMed:2427760]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Virus receptor activity
Specific Function
ICAM proteins are ligands for the leukocyte adhesion protein LFA-1 (integrin alpha-L/beta-2). During leukocyte trans-endothelial migration, ICAM1 engagement promotes the assembly of endothelial api...
Gene Name
ICAM1
Uniprot ID
P05362
Uniprot Name
Intercellular adhesion molecule 1
Molecular Weight
57824.785 Da
References
  1. Kang MW, Song HJ, Kang SK, Kim Y, Jung SB, Jee S, Moon JY, Suh KS, Lee SD, Jeon BH, Kim CS: Nafamostat Mesilate Inhibits TNF-alpha-Induced Vascular Endothelial Cell Dysfunction by Inhibiting Reactive Oxygen Species Production. Korean J Physiol Pharmacol. 2015 May;19(3):229-34. doi: 10.4196/kjpp.2015.19.3.229. Epub 2015 Apr 30. [PubMed:25954127]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Secondary active organic cation transmembrane transporter activity
Specific Function
Translocates a broad array of organic cations with various structures and molecular weights including the model compounds 1-methyl-4-phenylpyridinium (MPP), tetraethylammonium (TEA), N-1-methylnico...
Gene Name
SLC22A1
Uniprot ID
O15245
Uniprot Name
Solute carrier family 22 member 1
Molecular Weight
61153.345 Da
References
  1. Li Q, Sai Y, Kato Y, Muraoka H, Tamai I, Tsuji A: Transporter-mediated renal handling of nafamostat mesilate. J Pharm Sci. 2004 Feb;93(2):262-72. [PubMed:14705184]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Quaternary ammonium group transmembrane transporter activity
Specific Function
Mediates tubular uptake of organic compounds from circulation. Mediates the influx of agmatine, dopamine, noradrenaline (norepinephrine), serotonin, choline, famotidine, ranitidine, histamin, creat...
Gene Name
SLC22A2
Uniprot ID
O15244
Uniprot Name
Solute carrier family 22 member 2
Molecular Weight
62579.99 Da
References
  1. Li Q, Sai Y, Kato Y, Muraoka H, Tamai I, Tsuji A: Transporter-mediated renal handling of nafamostat mesilate. J Pharm Sci. 2004 Feb;93(2):262-72. [PubMed:14705184]

Drug created on October 20, 2016 17:07 / Updated on November 02, 2018 09:09