Nafamostat

Nafamostat mesylate (INN), a synthetic serine protease inhibitor, it is a short-acting anticoagulant,[1] and is also used for the treatment of pancreatitis. It also has some potential antiviral and anti-cancer properties.[2] Nafamostat is a fast-acting proteolytic inhibitor and used during hemodialysis to prevent the proteolysis of fibrinogen into fibrin.[3] The mechanism of action of Nafamostat is as a slow tight-binding substrate, trapping the target protein in the acyl-enzyme intermediate form, resulting in apparent observed inhibition. [4][5]

Nafamostat mesylate
Clinical data
AHFS/Drugs.comInternational Drug Names
Routes of
administration		IV
ATC code
  • none
Legal status
Legal status
  • In general: ℞ (Prescription only)
Identifiers
IUPAC name
  • 6-[amino(imino)methyl]-2-naphthyl 4-{[amino(imino)methyl]amino}benzoate
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC19H17N5O2
Molar mass347.378 g·mol−1
3D model (JSmol)
SMILES
  • C1=CC(=CC=C1C(=O)OC2=CC3=C(C=C2)C=C(C=C3)C(=N)N)N=C(N)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) N
  • Key:MQQNFDZXWVTQEH-UHFFFAOYSA-N N
 NY (what is this?)  (verify)

It inhibits a large number of Lys/Arg specific serine proteinases, and is also a tryptase inhibitor, which is implicated in leaking blood vessels which is symptomatic of dengue hemorrhagic fever and of end-stage dengue shock syndrome.[6] It is available in a generic form already used for the treatment of certain bleeding complications in some countries, there are risks of severe complications such as: agranulocytosis, hyperkalemia, and anaphylaxis which must be weighed in non-emergency care.[7] In some countries, it used as a treatment for pancreatitis and pancreatic cancer.

This drug has been identified as a potential therapy for COVID-19,[8] with clinical trials in Japan possibly set to begin in March 2020.[9] With evidence that Nafamostat is a potent anti-viral inhibitor in lung cells, a second round of clinical trials in Korea has begun with 10 hospitals participating.[10]

Multiple Phase 2/3[11][12][13] and Phase 3[14][15] clinical trials for COVID-19 in different countries are ongoing.

References
  1. Al-Horani RA, Desai UR (November 2014). "Recent advances on plasmin inhibitors for the treatment of fibrinolysis-related disorders". Medicinal Research Reviews. 34 (6): 1168–216. doi:10.1002/med.21315. PMC 8788159. PMID 24659483. S2CID 22631056.
  2. Chen X, Xu Z, Zeng S, Wang X, Liu W, Qian L, et al. (2019). "The Molecular Aspect of Antitumor Effects of Protease Inhibitor Nafamostat Mesylate and Its Role in Potential Clinical Applications". Frontiers in Oncology. 9: 852. doi:10.3389/fonc.2019.00852. PMC 6733886. PMID 31552177.
  3. Sadahiro T, Yuzawa H, Kimura T, Oguchi M, Morito T, Mizushima S, Hirose Y (2018). "Current Practices in Acute Blood Purification Therapy in Japan and Topics for Further Study". Contributions to Nephrology. 196: 209–214. doi:10.1159/000485724. ISBN 978-3-318-06297-7. PMID 30041229.
  4. Ramjee, M, Henderson, IJ, Sheila McLoughlin, SB & Padova, A (June 2000). "The kinetic and structural characterization of the reaction of nafamostat with bovine pancreatic trypsin". Thrombosis Research. 98 (6): 559–569. doi:10.1016/s0049-3848(00)00206-1. PMID 10899355.{{cite journal}}: CS1 maint: uses authors parameter (link)
  5. Ramjee, M & Patel, S (July 2017). "Continuous-flow injection microfluidic thrombin assays: The effect of binding kinetics on observed enzyme inhibition". Analytical Biochemistry. 528: 38–46. doi:10.1016/j.ab.2017.04.016. PMID 28456636.{{cite journal}}: CS1 maint: uses authors parameter (link)
  6. Rathore, Abhay P.S.; Mantri, Chinmay Kumar; Aman, Siti A.B.; Syenina, Ayesa; Ooi, Justin; Jagaraj, Cyril J.; Goh, Chi Ching; Tissera, Hasitha; Wilder-Smith, Annelies; Ng, Lai Guan; Gubler, Duane J. (2019-08-26). "Dengue virus–elicited tryptase induces endothelial permeability and shock". Journal of Clinical Investigation. 129 (10): 4180–4193. doi:10.1172/JCI128426. ISSN 0021-9738. PMC 6763290. PMID 31265436.
  7. PubChem. "Nafamostat". pubchem.ncbi.nlm.nih.gov. Retrieved 2020-06-17.
  8. Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. (March 2020). "Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro". Cell Research. 30 (3): 269–271. doi:10.1038/s41422-020-0282-0. PMC 7054408. PMID 32020029.
  9. "Japanese researchers to test blood thinner for coronavirus treatment". The Japan Times Online. 2020-03-19. ISSN 0447-5763. Retrieved 2020-03-24.
  10. Ltd, John Wiley & Sons; The Atrium, Southern Gate; Chichester; PO19 8SQ; Tel : 01243 779777; Fax : 01243 770421. "Korean researchers find drug that is more effective in treating COVID-19 than remdesivir | Pharmafile". www.pharmafile.com. Retrieved 2020-06-17.
  11. "Rapid Experimental Medicine for COVID-19 - Full Text View". ClinicalTrials.gov. 2020-07-16. Retrieved 2021-02-04.
  12. "Efficacy of Nafamostat in Covid-19 Patients (RACONA Study) - Full Text View". ClinicalTrials.gov. 2020-04-20. Retrieved 2021-02-04.
  13. "Clinical Efficacy of Nafamostat Mesylate for COVID-19 Pneumonia - Full Text View". ClinicalTrials.gov. 2020-06-05. Retrieved 2021-02-04.
  14. Tong, Associate Professor Steven (2020-07-23). "Australasian COVID-19 Trial (ASCOT) ADAptive Platform Trial - Full Text View". ClinicalTrials.gov. Retrieved 2021-02-04.
  15. "Efficacy and Safety Evaluation of Treatment Regimens in Adult COVID-19 Patients in Senegal - Full Text View". ClinicalTrials.gov. 2020-05-15. Retrieved 2021-02-04.
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