NAFAMOSTAT

Possibly Marketed Outside US

Details

Stereochemistry	ACHIRAL
Molecular Formula	C19H17N5O2
Molecular Weight	347.3706
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

NC(=N)NC1=CC=C(C=C1)C(=O)OC2=CC=C3C=C(C=CC3=C2)C(N)=N

InChI

InChIKey=MQQNFDZXWVTQEH-UHFFFAOYSA-N

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)

HIDE SMILES / InChI

Description
Sources: http://www.rad-ar.or.jp/siori/english/kekka.cgi?n=35600 | https://www.ncbi.nlm.nih.gov/pubmed/8713783 | https://www.ncbi.nlm.nih.gov/pubmed/8029816

Nafamostat mesilate (NM), a synthetic serine protease inhibitor, has anticoagulant and anti-inflammatory properties. Nafamostat is approved and marketed in Japan. It relieves symptoms such as pain due to inflammation of the spleen. It improves visceral disorders and bleeding tendency caused by blood clotting tendency in the vessels. It prevents coagulation in the blood circuit during hemodialysis. It is usually used to improve acute symptoms of pancreatitis (acute pancreatitis, acute exacerbation phase of chronic pancreatitis, post-operative acute pancreatitis, acute pancreatitis after pancreatography, traumatic pancreatitis) and to prevent disseminated intravascular coagulation (DIC) and clotting of perfusing blood in extracorporeal blood circuit. Nafamostat mesilate significantly inhibits the release of platelet beta-thromboglobulin (beta TG) at 60 and 120 min. Nafamostat mesilate (NM) prevents any significant release of neutrophil elastase; at 120 min, plasma elastase-alpha 1-antitrypsin complex is 0.16 mg/mL in the NM group and 1.24 mg/mL in the control group. Nafamostat mesilate completely inhibits formation of complexes of C1 inhibitor with kallikrein and FXIIa.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Trypsin I 2 Target ID: CHEMBL209 Sources: https://www.ncbi.nlm.nih.gov/pubmed/10206542 \| https://www.ncbi.nlm.nih.gov/pubmed/9544206	Inhibitor 8504	17.0 nM [IC50]
Complement C1r 2 Target ID: CHEMBL4611 Sources: https://www.ncbi.nlm.nih.gov/pubmed/10206542 \| https://www.ncbi.nlm.nih.gov/pubmed/9544206	Inhibitor 8504	12.0 µM [IC50]
Tryptase beta-1 2 Target ID: CHEMBL2617 Sources: https://www.ncbi.nlm.nih.gov/pubmed/12939527	Inhibitor 8504	95.3 pM [Ki]
Transient receptor potential cation channel subfamily M member 7 6 Target ID: CHEMBL1250412 Sources: https://www.ncbi.nlm.nih.gov/pubmed/21122141	Inhibitor 8504	617.0 µM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Pancreatitis 16 Sources: https://www.ncbi.nlm.nih.gov/pubmed/25822153 https://www.ncbi.nlm.nih.gov/pubmed/21206331	Primary		Approved 8583	NAFAMOSTAT Approved Use This medicine relieves symptoms such as pain due to inflammation of the spleen. It improves visceral disorders and bleeding tendency caused by blood clotting tendency in the vessels. It prevents coagulation in the blood circuit during hemodialysis. It is usually used to improve acute symptoms of pancreatitis (acute pancreatitis, acute exacerbation phase of chronic pancreatitis, post-operative acute pancreatitis, acute pancreatitis after pancreatography, traumatic pancreatitis) and to prevent disseminated intravascular coagulation (DIC) and clotting of perfusing blood in extracorporeal blood circuit.
Disseminated intravascular coagulation 8 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26466700 https://www.ncbi.nlm.nih.gov/pubmed/11372771	Preventing		Approved 8583	NAFAMOSTAT Approved Use This medicine relieves symptoms such as pain due to inflammation of the spleen. It improves visceral disorders and bleeding tendency caused by blood clotting tendency in the vessels. It prevents coagulation in the blood circuit during hemodialysis. It is usually used to improve acute symptoms of pancreatitis (acute pancreatitis, acute exacerbation phase of chronic pancreatitis, post-operative acute pancreatitis, acute pancreatitis after pancreatography, traumatic pancreatitis) and to prevent disseminated intravascular coagulation (DIC) and clotting of perfusing blood in extracorporeal blood circuit.

C_max

Value	Dose	Analyte	Population
16.4 ng/mL OTHER GOV'T https://www.info.pmda.go.jp/go/interview/2/530169_3999407D1181_2_008_1F.pdf#page=23	10 mg single, intravenous dose: 10 mg route of administration: Intravenous experiment type: SINGLE co-administered:	NAFAMOSTAT blood	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
61.5 ng/mL OTHER GOV'T https://www.info.pmda.go.jp/go/interview/2/530169_3999407D1181_2_008_1F.pdf#page=23	20 mg single, intravenous dose: 20 mg route of administration: Intravenous experiment type: SINGLE co-administered:	NAFAMOSTAT blood	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
93.2 ng/mL OTHER GOV'T https://www.info.pmda.go.jp/go/interview/2/530169_3999407D1181_2_008_1F.pdf#page=23	40 mg single, intravenous dose: 40 mg route of administration: Intravenous experiment type: SINGLE co-administered:	NAFAMOSTAT blood	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
14.49 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/18392693/	10 mg single, intravenous dose: 10 mg route of administration: Intravenous experiment type: SINGLE co-administered:	NAFAMOSTAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
40.4 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/18392693/	20 mg single, intravenous dose: 20 mg route of administration: Intravenous experiment type: SINGLE co-administered:	NAFAMOSTAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
60.43 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/18392693/	40 mg single, intravenous dose: 40 mg route of administration: Intravenous experiment type: SINGLE co-administered:	NAFAMOSTAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

AUC

Value	Dose	Analyte	Population
1655.84 ng × min/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/18392693/	10 mg single, intravenous dose: 10 mg route of administration: Intravenous experiment type: SINGLE co-administered:	NAFAMOSTAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
3571.14 ng × min/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/18392693/	20 mg single, intravenous dose: 20 mg route of administration: Intravenous experiment type: SINGLE co-administered:	NAFAMOSTAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
6880.46 ng × min/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/18392693/	40 mg single, intravenous dose: 40 mg route of administration: Intravenous experiment type: SINGLE co-administered:	NAFAMOSTAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

T_1/2

Value	Dose	Analyte	Population
23.1 min OTHER GOV'T https://www.info.pmda.go.jp/go/interview/2/530169_3999407D1181_2_008_1F.pdf#page=23	40 mg single, intravenous dose: 40 mg route of administration: Intravenous experiment type: SINGLE co-administered:	NAFAMOSTAT blood	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
112.42 min EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/18392693/	10 mg single, intravenous dose: 10 mg route of administration: Intravenous experiment type: SINGLE co-administered:	NAFAMOSTAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
128.19 min EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/18392693/	20 mg single, intravenous dose: 20 mg route of administration: Intravenous experiment type: SINGLE co-administered:	NAFAMOSTAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
122.91 min EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/18392693/	40 mg single, intravenous dose: 40 mg route of administration: Intravenous experiment type: SINGLE co-administered:	NAFAMOSTAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
33.36% OTHER GOV'T https://www.info.pmda.go.jp/go/interview/2/530169_3999407D1181_2_008_1F.pdf#page=24			NAFAMOSTAT serum	Homo sapiens

Doses

Dose	Population	Adverse events
20 mg single, intravenous Studied dose Dose: 20 mg Route: intravenous Route: single Dose: 20 mg Sources: https://pubmed.ncbi.nlm.nih.gov/33495919/	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/33495919/	Other AEs: Hyperkalemia... Other AEs: Hyperkalemia (0.7%) Sources: https://pubmed.ncbi.nlm.nih.gov/33495919/
50 mg single, intravenous Studied dose Dose: 50 mg Route: intravenous Route: single Dose: 50 mg Sources: https://pubmed.ncbi.nlm.nih.gov/21775918/	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/21775918/	Sources: https://pubmed.ncbi.nlm.nih.gov/21775918/
1200 ug/kg/h single, intravenous Studied dose Dose: 1200 ug/kg/h Route: intravenous Route: single Dose: 1200 ug/kg/h Sources: https://pubmed.ncbi.nlm.nih.gov/1554918/	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/1554918/	Sources: https://pubmed.ncbi.nlm.nih.gov/1554918/

AEs

AE	Significance	Dose	Population
Hyperkalemia	0.7%	20 mg single, intravenous Studied dose Dose: 20 mg Route: intravenous Route: single Dose: 20 mg Sources: https://pubmed.ncbi.nlm.nih.gov/33495919/	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/33495919/

Overview

CYP3A4	CYP2C9	CYP2D6	hERG

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
	OCT2 434 P-gp 2052 OCTN1 55 OCTN2 59

Drug as victim

Target	Modality	Activity
OCTN1 55	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/14705184/	no
OCTN2 59	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/14705184/	no
P-gp 2052	substrate 4014 Sources: https://www.ebi.ac.uk/chembl/g/#browse/activities/full_state/eyJsaXN0Ijp7InNldHRpbmdzX3BhdGgiOiJFU19JTkRFWEVTX05PX01BSU5fU0VBUkNILkFDVElWSVRZIiwiY3VzdG9tX3F1ZXJ5IjoidGFyZ2V0X2NoZW1ibF9pZDpDSEVNQkw0MzAyIiwidXNlX2N1c3RvbV9xdWVyeSI6dHJ1ZSwic2VhcmNoX3Rlcm0iOiIiLCJ0ZXh0X2ZpbHRlciI6IkNIRU1CTDEwOTE4NDEifX0=	no
OCT2 434	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/14705184/	yes [IC50 20 uM]

PubMed

Title	Date	PubMed
[Fulminant myocarditis treated with percutaneous cardiopulmonary support and long-term complications: three case reports].	2004 Apr	15125383
A serine protease inhibitor, nafamostat mesilate, suppresses aldosterone secretions in vivo.	2004 Dec	15894839
Detection of specific IgE antibodies to nafamostat mesilate as an indication of possible adverse effects of leukocytapheresis using nafamostat mesilate as anticoagulant.	2004 Feb	15128019
Intraoperative management of a congenital antithrombin deficient patient on chronic hemodialysis.	2004 Jul	15213863
Inhibition of enteral enzymes by enteroclysis with nafamostat mesilate reduces neutrophil activation and transfusion requirements after hemorrhagic shock.	2004 Mar	15128119
[Anticoagulant].	2004 May	15197947
[Anticoagulation for plasmapheresis].	2004 May	15197938
[How to use anticoagulants in hemodialysis therapy].	2004 May	15197908
[Changes in coagulation, fibrinolysis and platelet functions during extracorporeal circulation].	2004 May	15197886
Efficacy of continuous regional arterial infusion of a protease inhibitor and antibiotic for severe acute pancreatitis in patients admitted to an intensive care unit.	2004 May	15097852
Effects of anti-inflammatory cytokine agent (FR167653) and serine protease inhibitor on warm ischemia-reperfusion injury of the liver graft.	2004 May 27	15239609
[Treatment of acute pancreatitis with protease inhibitor, H2 receptor antagonist and somatostatin analogue].	2004 Nov	15552889
Continuous hemodiafiltration in pediatric critical care patients.	2004 Oct	15663534
Advanced glycation end products induce secretion of chemokines and apoptosis in human first trimester trophoblasts.	2004 Sep	15243005
Nafamostat preserves neutrophil deformability and reduces microaggregate formation during simulated extracorporeal circulation.	2005 Apr	15797071
Correlation between serum nafamostat mesilate and activated coagulation time during continuous hemodiafiltration.	2005 Apr	15787634
Rat experimental model of continuous regional arterial infusion of protease inhibitor and its effects on severe acute pancreatitis.	2005 Apr	15782103
Small volume resuscitation with hypertonic saline is more effective in ameliorating trauma-hemorrhagic shock-induced lung injury, neutrophil activation and red blood cell dysfunction than pancreatitic protease inhibition.	2005 Aug	16294064
Mast cell tryptase stimulates DLD-1 carcinoma through prostaglandin- and MAP kinase-dependent manners.	2005 Aug	16093613
Nafamostat mesilate induces production of interleukin-12 and -18 in human peripheral blood mononuclear cells.	2005 Aug	16093612
Effect of intraportal infusion to improve small for size graft injury in living donor adult liver transplantation.	2005 Aug	16008741
[A patient with Vibrio vulnificus meningoencephalitis].	2005 Jan	15714995
Open heart surgery in a patient with paroxysmal nocturnal hemoglobinuria.	2005 Jun	15997761
Involvement of neutrophil recruitment and protease-activated receptor 2 activation in the induction of IL-18 in mice.	2005 Nov	16260585
JPN Guidelines for the management of acute pancreatitis: medical management of acute pancreatitis.	2006	16463210
Involvement of human blood arylesterases and liver microsomal carboxylesterases in nafamostat hydrolysis.	2006 Apr	16702735
Nafamostat attenuated the impairment of fibrinolysis in animal sepsis model by suppressing the increase of plasminogen activator inhibitor type 1.	2006 Apr	16612309
Anti-tryptase treatment using nafamostat mesilate has a therapeutic effect on experimental colitis.	2006 Aug	16803693
Implantation Serine Proteinases heterodimerize and are critical in hatching and implantation.	2006 Dec 11	17156484
Leukocytapheresis for ulcerative colitis: a comparative study of anticoagulant (nafamostat mesilate vs. dalteparin sodium) for reducing clinical complications.	2006 Feb	16556137
[Quality of life in surgical treatment of pancreatic cancer].	2006 Jan	16457272
Myeloperoxidase as a marker of hemodialysis biocompatibility and oxidative stress: the underestimated modifying effects of heparin.	2006 Jan	16377383
Potent pruritogenic action of tryptase mediated by PAR-2 receptor and its involvement in anti-pruritic effect of nafamostat mesilate in mice.	2006 Jan 13	16359660
The role of a protease inhibitor against hepatectomy.	2006 Jan-Feb	16506388
[Prostasin].	2006 Jul	16895180
Serine protease inhibitors nafamostat mesilate and gabexate mesilate attenuate allergen-induced airway inflammation and eosinophilia in a murine model of asthma.	2006 Jul	16815145
Anticoagulation and continuous renal replacement therapy.	2006 Jul-Aug	16893409
Topical application of epidermal growth factor accelerates wound healing by myofibroblast proliferation and collagen synthesis in rat.	2006 Jun	16645332
Human complement-activating immunoglobulin (Ig)G3 antibodies are essential for porcine endothelial cell activation.	2006 May	16756564
[Postoperative acute pulmonary thromboembolism treated with nafamostat mesilate].	2006 May	16715921
Complement activation is involved in biological responses to leukocyte adsorptive apheresis.	2006 May	16642423
Properties of poly(lactic-co-glycolic acid) nanospheres containing protease inhibitors: camostat mesilate and nafamostat mesilate.	2006 May 11	16551494
Effects of nafamostat mesilate on ADP-induced platelet aggregation and disaggregation in hemodialysis patients.	2006 May-Jun	16760715
Protective effects of nafamostat mesilate on liver injury induced by lipopolysaccharide in rats: possible involvement of CD14 and TLR-4 downregulation on Kupffer cells.	2006 Nov	17072764
Nafamostat mesilate inhibits high-mobility group box 1 by lipopolysaccharide stimulation in murine macrophage RAW 264.7.	2007 Apr	17414427
Antitumor effects of Nafamostat mesilate on head and neck squamous cell carcinoma.	2007 Dec	17337140
[Anticoagulation of extracorporeal circuit in critically ill patients].	2007 Jan-Feb	17342691
Pancreatic enzymes generate cytotoxic mediators in the intestine.	2007 Mar	17304111
Low-volume continuous hemodiafiltration with nafamostat mesilate increases trypsin clearance without decreasing plasma trypsin concentration in severe acute pancreatitis.	2007 Mar-Apr	17413562
Mechanisms of synthetic serine protease inhibitor (FUT-175)-mediated cell death.	2007 May 15	17410536

Patents

Sample Use Guides

In Vivo Use Guide

Acute Kidney Injury: Initial dose of nafamostat mesilate is 20mg/hr. Dosage is adjusted from 10mg to 30mg/hr according to patients' status. For priming, two vial of nafamostat mesilate was dissolved in 2mL of 5% glucose fluid, and then mixed with 1000mL of normal saline. After carefully removing air bubble from the circuit with the prepared fluid, nafamostat mesilate was dissolved with 15 mL of 5% glucose fluid and loaded in anticoagulation line with starting dose of 20mg/hr.

Route of Administration: Intravenous

In Vitro Use Guide

Nafamostat inhibited extrinsic pathway activity (TF-F.VIIa mediated-F.Xa generation) in a concentration dependent manner; the IC50 was 1.0 x 10(-7) M. Nafamostat inhibited TF-F.VIIa complex activity with an IC50 of 1.5 x 10(-7) M.

Name

Type

Language

BENZOIC ACID, 4-((AMINOIMINOMETHYL)AMINO)-, 6-(AMINOIMINOMETHYL)-2-NAPHTHALENYL ESTER

Preferred Name

English

NAFAMOSTAT

Official Name

English

Nafamostat [WHO-DD]

Common Name

English

nafamostat [INN]

Common Name

English

NAFAMOSTAT [MI]

Common Name

English

Classification Tree Code System Code

FDA ORPHAN DRUG

835721