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
Thumb
Synonyms
Not Available
External IDs
SIGA-246 / ST 246 / ST-246
Product Ingredients
IngredientUNIICASInChI Key
Tecovirimat monohydrateSB96YO2BR81162664-19-8QRHXYGPOQKLBJP-NPIFKJBVSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
TpoxxCapsule200 mg/1OralSIGA Technologies, Inc.2018-08-31Not applicableUs
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].

TargetActionsOrganism
AEnvelope protein F13
inhibitor
Variola 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
DrugInteraction
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
  1. 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]
  2. 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]
  3. 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]
  4. 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]
  5. 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]
  6. 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]
  7. FDA approves the first drug with an indication for treatment of smallpox [Link]
  8. FDA approves first smallpox indicated treatment [Link]
  9. 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
PhaseStatusPurposeConditionsCount
1CompletedTreatmentHealthy Volunteers1
1CompletedTreatmentMonkey Pox / Orthopoxviral Disease / Smallpox1
2CompletedNot AvailableOrthopoxviral Disease1
3CompletedTreatmentOrthopoxvirus / Smallpox1
Not AvailableAvailableNot AvailableMonkeypox / Smallpox1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
CapsuleOral200 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US7737168No2007-05-032027-05-03Us
US8802714No2004-06-182024-06-18Us
US8530509No2004-06-182024-06-18Us
US9339466No2011-03-232031-03-23Us
US8124643No2004-06-182024-06-18Us
US8039504No2007-07-232027-07-23Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)194-195MSDS
water solubilityinsoluble https://medkoo.com/products/8132
logP2.73210MSDS
Predicted Properties
PropertyValueSource
Water Solubility0.021 mg/mLALOGPS
logP2.03ALOGPS
logP2.07ChemAxon
logS-4.2ALOGPS
pKa (Strongest Acidic)9.15ChemAxon
pKa (Strongest Basic)-6.2ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area66.48 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity89.45 m3·mol-1ChemAxon
Polarizability34.02 Å3ChemAxon
Number of Rings5ChemAxon
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 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
  1. 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]
  2. 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]
  3. FDA advisory committee meeting [File]

Enzymes

Kind
Protein
Organism
Human
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
Human
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 November 02, 2018 09:16