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

Similar Structures

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
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Tpoxx	Capsule	200 mg/1	Oral	SIGA Technologies, Inc.	2018-08-31	Not applicable

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Application Number

A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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Product Code

A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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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

Tecovirimat is indicated for the treatment of smallpox infection. It can be administered in children and adults with a minimum body weight of 13 kg ^Label. Tecovirimat is an inhibitor of the Orthopoxvirus VP37 envelope wrapping protein ^Label.

Associated Conditions

Smallpox

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	inhibitor	Variola virus (isolate Human/India/Ind3/1967)

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Adverse Effects

Comprehensive structured data on known drug adverse effects with statistical prevalence. MedDRA and ICD10 ids are provided for adverse effect conditions and symptoms.

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Contraindications

Structured data covering drug contraindications. Each contraindication describes a scenario in which the drug is not to be used. Includes restrictions on co-administration, contraindicated populations, and more.

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Blackbox Warnings

Structured data representing warnings from the black box section of drug labels. These warnings cover important and dangerous risks, contraindications, or adverse effects.

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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

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

Drug	Interaction
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Adenine	The metabolism of Tecovirimat can be decreased when combined with Adenine.
Adenovirus type 7 vaccine live	The therapeutic efficacy of Adenovirus type 7 vaccine live can be decreased when used in combination with Tecovirimat.
Amitriptyline	The metabolism of Tecovirimat can be decreased when combined with Amitriptyline.
Anthrax vaccine	The therapeutic efficacy of Anthrax vaccine can be decreased when used in combination with Tecovirimat.
Atazanavir	The metabolism of Tecovirimat can be decreased when combined with Atazanavir.
Bacillus calmette-guerin substrain connaught live antigen	The therapeutic efficacy of Bacillus calmette-guerin substrain connaught live antigen can be decreased when used in combination with Tecovirimat.
Bacillus calmette-guerin substrain danish 1331 live antigen	The therapeutic efficacy of Bacillus calmette-guerin substrain danish 1331 live antigen can be decreased when used in combination with Tecovirimat.
Bacillus calmette-guerin substrain tice live antigen	The therapeutic efficacy of Bacillus calmette-guerin substrain tice live antigen can be decreased when used in combination with Tecovirimat.
BCG vaccine	The therapeutic efficacy of BCG vaccine can be decreased when used in combination with Tecovirimat.
Carbamazepine	The metabolism of Tecovirimat can be increased when combined with Carbamazepine.

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Extended Description

Extended description of the mechanism of action and particular properties of each drug interaction.

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Severity

A severity rating for each drug interaction, from minor to major.

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Evidence Level

A rating for the strength of the evidence supporting each drug interaction.

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Action

An effect category for each drug interaction. Know how this interaction affects the subject drug.

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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
1	Withdrawn	Treatment	Vaccinia	1
2	Completed	Not Available	Orthopoxviral Disease	1
3	Completed	Treatment	Orthopoxvirus / Smallpox	1
Not Available	Available	Not Available	Monkeypox / Smallpox	1
Not Available	Not Yet Recruiting	Not Available	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)
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US7737168	No	2010-06-15	2027-05-03
US8802714	No	2014-08-12	2024-06-18
US8530509	No	2013-09-10	2024-06-18
US9339466	No	2016-05-17	2031-03-23
US8124643	No	2012-02-28	2024-06-18
US8039504	No	2011-10-18	2027-07-23

Additional Data Available

Filed On

The date on which a patent was filed with the relevant government.

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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
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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

Details1. Envelope protein F13

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

Details1. UDP-glucuronosyltransferase 1-1

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate

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

References

Tecovirimat FDA label [Link]

Details2. UDP-glucuronosyltransferase 1-4

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate

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

References

Tecovirimat FDA label [Link]

Drug created on October 20, 2016 15:11 / Updated on December 02, 2019 09:16

Tecovirimat

Identification

Structure for Tecovirimat (DB12020)

Pharmacology

Interactions

References

Clinical Trials

Pharmacoeconomics

Properties

Spectra

Taxonomy

Targets

References

Enzymes

References

References