Tecovirimat
Identification
- Name
- Tecovirimat
- Accession Number
- DB12020 (DB06000)
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Description
The World Health Organization declared smallpox, a contagious and sometimes fatal infectious disease, eradicated in 1980. However, there have been longstanding concerns that smallpox may be used as a bioweapon [7].
Also known as ST-246, Tecovirimat is the first approved drug for smallpox [8], [7].
Tecovirimat has been studied for the treatment of smallpox, monkeypox, orthopoxvirus, and orthopoxviral Disease. The U.S. Food and Drug Administration approved tecovirimat (as TPOXX) on July 13, 2018 for the treatment of smallpox [7].
- Structure
Structure for Tecovirimat (DB12020)
- Synonyms
- Tecovirimat
- External IDs
- SIGA-246 / ST 246 / ST-246
- Product Ingredients
Ingredient UNII CAS InChI Key Tecovirimat monohydrate SB96YO2BR8 1162664-19-8 QRHXYGPOQKLBJP-NPIFKJBVSA-N - Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Tpoxx Capsule 200 mg/1 Oral SIGA Technologies, Inc. 2018-08-31 Not applicable US 
- Categories
- UNII
- F925RR824R
- CAS number
- 869572-92-9
- Weight
- Average: 376.335
Monoisotopic: 376.10347684 - Chemical Formula
- C19H15F3N2O3
- InChI Key
- CSKDFZIMJXRJGH-VWLPUNTISA-N
- InChI
- InChI=1S/C19H15F3N2O3/c20-19(21,22)9-3-1-8(2-4-9)16(25)23-24-17(26)14-10-5-6-11(13-7-12(10)13)15(14)18(24)27/h1-6,10-15H,7H2,(H,23,25)/t10-,11+,12+,13-,14-,15+
- IUPAC Name
- N-[(1R,2R,6S,7S,8S,10R)-3,5-dioxo-4-azatetracyclo[5.3.2.0^{2,6}.0^{8,10}]dodec-11-en-4-yl]-4-(trifluoromethyl)benzamide
- SMILES
- FC(F)(F)C1=CC=C(C=C1)C(=O)NN1C(=O)[C@H]2[C@H]([C@H]3C=C[C@@H]2[C@@H]2C[C@H]32)C1=O
Pharmacology
- Indication
Smallpox virus infection is an inhibitor of the orthopoxvirus VP37 envelope wrapping protein and is indicated for the treatment of human smallpox disease in adults and pediatric patients weighing at least 13 kg [Label].
- Associated Conditions
- Pharmacodynamics
Tecovirimat prevents viral spread throughout the body [9]. This drug inhibits its molecular target, a protein called p37, from interacting with intracellular transport components necessary for the production of enveloped virus, and therefore the spread of virus [9].
- Mechanism of action
Tecovirimat inhibits the production of extracellular viral forms, which are responsible for the systemic spread of infection, inhibiting virus-induced cytopathic effects. Tecovirimat does not inhibit the formation of intracellular forms of the virus (IMV); however, by inhibiting envelopment, and therefore preventing the exit of viral particles from an infected cell, the smallpox infection is slowed to a point where the immune system can eliminate the virus [9].
Tecovirimat has shown a high level of selectivity and specificity for orthopoxviruses. Tecovirimat targets the viral p37 protein, a highly conserved protein with no homologs outside of the Orthopoxvirus genus, inhibiting its function that is necessary for required for the viral envelopment of IMV (intracellular mature virus). Tecovirimat interferes with the cellular localization of p37 viral protein and prevents its association with cellular proteins involved in membrane trafficking [9].
Target Actions Organism AEnvelope protein F13 inhibitorVariola virus (isolate Human/India/Ind3/1967) - Absorption
Readily absorbed following oral administration, with mean times to maximum concentration from 3 to 4 h [3]. A study was conducted to determine the safety, tolerability, and pharmacokinetics of ST-246 administered as a single daily oral dose. Steady state was reached by day 6 (within 3 to 5 half-lives)[4].
- Volume of distribution
Approximately 1,356 L. Following oral administration in mice, [14C]-tecovirimat was distributed to all tissues analyzed with the highest concentrations noted in liver and gallbladder, respiratory tract tissues (i.e., nasal turbinates), and bone marrow. Studies in dogs and NHPs suggest that tecovirimat crosses the blood-brain barrier [9].
- Protein binding
Approximately 80% [9].
- Metabolism
In vitro studies indicate that tecovirimat is not a substrate of major cytochrome P450 (CYP) enzymes, but it is a substrate of human recombinant UGTs (specifically of UGT1A1 and 1A4) [Label].
Tecovirimat was found to be metabolized into 3 most abundant metabolites, M4, M5 and TFMBA, which do not have pharmacological activity [Label].
- Route of elimination
Less than 0.02% of the drug is excreted unchanged in the kidney, with a majority of the drug being excreted in glucuronidated form. Approximately 23% of unchanged drug is found in the feces [9].
- Half life
Approximately 20h [9].
- Clearance
Mainly renal [9].
- Toxicity
Tecovirimat has demonstrated to be well tolerated, with no serious adverse events (AEs). Common adverse reactions in healthy adult subjects (≥ 2%) were headache, nausea, abdominal pain, and vomiting [Label], [5].
Co-administration of repaglinide and tecovirimat may cause mild to moderate hypoglycemia [Label].
Oral administration of tecovirimat is generally well-tolerated at dose levels up to 2,000 mg/kg/day (mice) [9].
- Affected organisms
- Humans and other mammals
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
Drug Interaction Influenza a virus a/california/7/2009 (h1n1) live (attenuated) antigen The therapeutic efficacy of Influenza a virus a/california/7/2009 (h1n1) live (attenuated) antigen can be decreased when used in combination with Tecovirimat. Influenza a virus a/perth/16/2009 (h3n2) live (attenuated) antigen The therapeutic efficacy of Influenza a virus a/perth/16/2009 (h3n2) live (attenuated) antigen can be decreased when used in combination with Tecovirimat. Influenza Vaccine (Live/Attenuated) The therapeutic efficacy of Tecovirimat can be decreased when used in combination with Influenza Vaccine (Live/Attenuated). Varicella Zoster Vaccine (Live/Attenuated) The therapeutic efficacy of Varicella Zoster Vaccine (Live/Attenuated) can be decreased when used in combination with Tecovirimat. - Food Interactions
- Not Available
References
- General References
- Grosenbach DW, Honeychurch K, Rose EA, Chinsangaram J, Frimm A, Maiti B, Lovejoy C, Meara I, Long P, Hruby DE: Oral Tecovirimat for the Treatment of Smallpox. N Engl J Med. 2018 Jul 5;379(1):44-53. doi: 10.1056/NEJMoa1705688. [PubMed:29972742]
- Berhanu A, Prigge JT, Silvera PM, Honeychurch KM, Hruby DE, Grosenbach DW: Treatment with the smallpox antiviral tecovirimat (ST-246) alone or in combination with ACAM2000 vaccination is effective as a postsymptomatic therapy for monkeypox virus infection. Antimicrob Agents Chemother. 2015 Jul;59(7):4296-300. doi: 10.1128/AAC.00208-15. Epub 2015 Apr 20. [PubMed:25896687]
- Grosenbach DW, Jordan R, Hruby DE: Development of the small-molecule antiviral ST-246 as a smallpox therapeutic. Future Virol. 2011 May;6(5):653-671. doi: 10.2217/fvl.11.27. [PubMed:21837250]
- Jordan R, Chinsangaram J, Bolken TC, Tyavanagimatt SR, Tien D, Jones KF, Frimm A, Corrado ML, Pickens M, Landis P, Clarke J, Marbury TC, Hruby DE: Safety and pharmacokinetics of the antiorthopoxvirus compound ST-246 following repeat oral dosing in healthy adult subjects. Antimicrob Agents Chemother. 2010 Jun;54(6):2560-6. doi: 10.1128/AAC.01689-09. Epub 2010 Apr 12. [PubMed:20385870]
- Mucker EM, Goff AJ, Shamblin JD, Grosenbach DW, Damon IK, Mehal JM, Holman RC, Carroll D, Gallardo N, Olson VA, Clemmons CJ, Hudson P, Hruby DE: Efficacy of tecovirimat (ST-246) in nonhuman primates infected with variola virus (Smallpox). Antimicrob Agents Chemother. 2013 Dec;57(12):6246-53. doi: 10.1128/AAC.00977-13. Epub 2013 Oct 7. [PubMed:24100494]
- Duraffour S, Andrei G, Snoeck R: Tecovirimat, a p37 envelope protein inhibitor for the treatment of smallpox infection. IDrugs. 2010 Mar;13(3):181-91. [PubMed:20191435]
- FDA approves the first drug with an indication for treatment of smallpox [Link]
- FDA approves first smallpox indicated treatment [Link]
- FDA advisory committee meeting [File]
- External Links
- PubChem Compound
- 16124688
- PubChem Substance
- 347828336
- ChemSpider
- 17281586
- ChEMBL
- CHEMBL1257073
- Wikipedia
- Tecovirimat
- FDA label
- Download (687 KB)
- MSDS
- Download (72.1 KB)
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 1 Completed Treatment Healthy Volunteers 1 1 Completed Treatment Monkey Pox / Orthopoxviral Disease / Smallpox 1 2 Completed Not Available Orthopoxviral Disease 1 3 Completed Treatment Orthopoxvirus / Smallpox 1 Not Available Available Not Available Monkeypox / Smallpox 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage forms
Form Route Strength Capsule Oral 200 mg/1 - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) US7737168 No 2010-06-15 2027-05-03 US US8802714 No 2014-08-12 2024-06-18 US US8530509 No 2013-09-10 2024-06-18 US US9339466 No 2016-05-17 2031-03-23 US US8124643 No 2012-02-28 2024-06-18 US US8039504 No 2011-10-18 2027-07-23 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) 194-195 MSDS water solubility insoluble https://medkoo.com/products/8132 logP 2.73210 MSDS - Predicted Properties
Property Value Source Water Solubility 0.021 mg/mL ALOGPS logP 2.03 ALOGPS logP 2.07 ChemAxon logS -4.2 ALOGPS pKa (Strongest Acidic) 9.15 ChemAxon pKa (Strongest Basic) -6.2 ChemAxon Physiological Charge 0 ChemAxon Hydrogen Acceptor Count 3 ChemAxon Hydrogen Donor Count 1 ChemAxon Polar Surface Area 66.48 Å2 ChemAxon Rotatable Bond Count 3 ChemAxon Refractivity 89.45 m3·mol-1 ChemAxon Polarizability 34.02 Å3 ChemAxon Number of Rings 5 ChemAxon Bioavailability 1 ChemAxon Rule of Five Yes ChemAxon Ghose Filter Yes ChemAxon Veber's Rule No ChemAxon MDDR-like Rule No ChemAxon - Predicted ADMET features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted GC-MS Spectrum - GC-MS Predicted GC-MS Not Available Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS Not Available
Taxonomy
- Description
- This compound belongs to the class of organic compounds known as isoindolones. These are aromatic polycyclic compounds that an isoindole bearing a ketone.
- Kingdom
- Organic compounds
- Super Class
- Organoheterocyclic compounds
- Class
- Isoindoles and derivatives
- Sub Class
- Isoindolines
- Direct Parent
- Isoindolones
- Alternative Parents
- Trifluoromethylbenzenes / Benzoic acids and derivatives / Benzoyl derivatives / Pyrrolidine-2-ones / Dicarboximides / Lactams / Carboxylic acid hydrazides / Azacyclic compounds / Organonitrogen compounds / Organofluorides show 4 more
- Substituents
- Trifluoromethylbenzene / Isoindolone / Benzoic acid or derivatives / Benzoyl / Monocyclic benzene moiety / Benzenoid / 2-pyrrolidone / Pyrrolidone / Pyrrolidine / Dicarboximide show 16 more
- Molecular Framework
- Aromatic heteropolycyclic compounds
- External Descriptors
- Not Available
Targets
- Kind
- Protein
- Organism
- Variola virus (isolate Human/India/Ind3/1967)
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Envelope protein associated with the inner side of the enveloped virion (EV) membrane.
- Specific Function
- Catalytic activity
- Gene Name
- Not Available
- Uniprot ID
- P33815
- Uniprot Name
- Envelope protein F13
- Molecular Weight
- 41902.245 Da
References
- Duraffour S, Andrei G, Snoeck R: Tecovirimat, a p37 envelope protein inhibitor for the treatment of smallpox infection. IDrugs. 2010 Mar;13(3):181-91. [PubMed:20191435]
- Mucker EM, Goff AJ, Shamblin JD, Grosenbach DW, Damon IK, Mehal JM, Holman RC, Carroll D, Gallardo N, Olson VA, Clemmons CJ, Hudson P, Hruby DE: Efficacy of tecovirimat (ST-246) in nonhuman primates infected with variola virus (Smallpox). Antimicrob Agents Chemother. 2013 Dec;57(12):6246-53. doi: 10.1128/AAC.00977-13. Epub 2013 Oct 7. [PubMed:24100494]
- FDA advisory committee meeting [File]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- General Function
- Steroid binding
- Specific Function
- UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX-alpha to form both the...
- Gene Name
- UGT1A1
- Uniprot ID
- P22309
- Uniprot Name
- UDP-glucuronosyltransferase 1-1
- Molecular Weight
- 59590.91 Da
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- General Function
- Protein homodimerization activity
- Specific Function
- UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX-alpha to form both the...
- Gene Name
- UGT1A4
- Uniprot ID
- P22310
- Uniprot Name
- UDP-glucuronosyltransferase 1-4
- Molecular Weight
- 60024.535 Da
Drug created on October 20, 2016 15:11 / Updated on December 16, 2018 06:59