Tapinarof

Identification

Summary

Tapinarof is a therapeutic aryl hydrocarbon receptor-modulating agent (TAMA) indicated for the treatment of adult psoriasis.

Brand Names

Vtama

Generic Name

Tapinarof

DrugBank Accession Number

DB06083

Background

Tapinarof is a novel, first-in-class, small-molecule AhR agonist that is indicated for the treatment of adult psoriasis. It is available as a topical cream to be applied to the affected area once daily.^11,7 Tapiranof was first discovered as a metabolite (3,5-dihydroxy-4-isopropylstilbene) produced in Photorhabdus luminescens, a gram-negative bacillus that lives symbiotically with the Heterorhabditis nematodes.⁷ In 1959, it was noticed that Heterorhabditis with a high amount of 3,5-dihydroxy-4-isopropylstilbene did not putrefy once dead, thus suggesting its potential anti-inflammatory activity.⁷

Tapinarof received initial approval from the FDA in 2022.¹¹

Type

Small Molecule

Groups

Approved, Investigational

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Tapinarof (DB06083)

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Weight

Average: 254.329
Monoisotopic: 254.13067982

Chemical Formula

C₁₇H₁₈O₂

Synonyms

• 3,5-Dihydroxy-4-isopropyl-trans-stilbene
• Benvitimod
• Tapinarof

External IDs

• GSK-2894512
• GSK2894512
• WBI 1001
• WBI-1001

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Pharmacology

Indication

Tapinarof is indicated for the topical treatment of plaque psoriasis in adults.¹¹

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Management of	Psoriasis vulgaris (plaque psoriasis)		••••••••••••	•••••		•••••

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Pharmacodynamics

The pharmacodynamics of tapinarof are unknown.¹¹

Mechanism of action

Tapinarof is a therapeutic aryl hydrocarbon receptor-modulating agent (TAMA) that binds to and activates the aryl hydrocarbon receptor (AhR). AhR is a ligand-dependent transcription factor that regulates gene expression in a variety of cell types, including macrophages, T-cells, antigen-presenting cells, fibroblasts, and keratinocytes.⁷ Upon binding to its ligand, AhR heterodimerizes with AhR nuclear translocator (ARNT) to form a complex with a high affinity for DNA binding.^7,4 The AhR-ligand/ARNT complex can then bind to the specific DNA recognition sites to transcribe AhR-responsive genes.^7,4 Additionally, AhR also exerts its effect through other transcription factors such as the nuclear factor κB and nuclear factor erythroid 2-related factor 2 (Nrf2), a downstream product of AhR-induced transcription that has antioxidant properties.^8,7

Dysregulation of AhR is one of the hallmarks of psoriasis, as psoriasis patients have a higher serum concentration of AhR compared to healthy individuals.⁶ Treatment of AhR ligands in vitro also results in a gene expression profile that is implicated in the pathogenesis of psoriasis.^6,4 For instance, AhR activation causes the expansion and differentiation of Th17 and Th22, two major T cells responsible for releasing inflammatory cytokines IL-17 and IL-22.^9,6,4. Additionally, AhR activation also recruits persistent skin resident memory T cells, thus contributing to the chronicity of psoriasis.¹⁰ However, the specific binding of tapinarof to AhR modulates a unique set of genes that are dysregulated in psoriasis, distinctive from other AhR ligands.^4,7 Further, tapinarof also induces barrier protein expression, such as filaggrin, hornerin, and involucrin, to restore the skin barrier and epidermal function and decrease oxidative stress.^7,6,10 It is currently unknown why AhR ligands like tapinarof can reduce psoriatic inflammations in one setting but upregulate inflammatory genes in another setting.⁴

It is possible that the anti-inflammatory effect of tapinarof as an AhR agonist might be due to Nrf2.⁴ Although Nrf2 is a known downstream effector of AhR, not all AhR agonists activate this pathway. For instance, 2,3,7,8-tetrachlorodibenzo-p-dioxin, an AhR agonist, does not show any antioxidant activity after AhR activation.⁵ Therefore, it is hypothesized that the dual AhR/Nrf2 action of tapinarof is essential to the effect of tapinarof in treating psoriasis.⁶

Target	Actions	Organism
AAryl hydrocarbon receptor	agonist	Humans

Absorption

No accumulation was observed with repeat topical application. Plasma concentration of tapinarof was below the quantifiable limits (BQL) of the assay (lower limit of quantification was 50 pg/mL) in 68% of the pharmacokinetic samples. On Day 1, mean ± SD values of Cmax and AUC0-last were 0.90 ± 1.4 ng/mL and 4.1 ± 6.3 ng.h/mL, respectively, following a mean daily dose of 5.23 g applied to a mean body surface area involvement of 27.2% (range 21 to 46%) in 21 subjects with moderate to severe plaque psoriasis. On Day 29, the mean ± SD Cmax and AUC0-last were 0.12 ± 0.15 ng/mL and 0.61 ± 0.65 ng.h/mL, respectively.¹¹

Volume of distribution

The Vss of tapinarof is estimated to be from 1270 to 1500 mL/kg.³

Protein binding

Human plasma protein binding of tapinarof is approximately 99% in vitro.¹¹

Metabolism

Tapinarof is metabolized in the liver by multiple pathways including oxidation, glucuronidation, and sulfation in vitro.¹¹CYP1A2 and CYP3A4 appears to be the major enzyme involved in the hepatic metabolism of tapinarof, while CYP2C9, CYP2C19, and CYP2D6 play a minor role.³

Route of elimination

Not Available

Half-life

Due to the insufficient data about the elimination phase, the terminal half-life of tapinarof cannot be determined.³

Clearance

Not Available

Adverse Effects

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Toxicity

Long-term carcinogenicity studies were conducted in mice (daily topical administration at doses of 0.5, 1.5, and 3% tapinarof cream) and in rats (subcutaneous administration at doses of 0.1, 0.3, and 1 mg/kg/day tapinarof). No drug-related neoplasms were noted in mice after 98 (females) to 102 (males) weeks of daily topical administration at doses up to 3% tapinarof cream (44 times the MRHD based on AUC comparisons). No drug-related neoplasms were noted in female rats after 83 weeks of daily subcutaneous administration at up to 1 mg/kg/day tapinarof (9 times the MRHD based on AUC comparisons).¹¹

Tapinarof revealed no evidence of mutagenicity or clastogenicity in an Ames assay, an in vitro mammalian chromosomal aberration assay, an in vitro mouse lymphoma assay, and two in vivo micronucleus assays in mice and rats.¹¹

Tapinarof did not impair female fertility at subcutaneous doses up to 30 mg/kg/day (268 times the MRHD based on AUC comparisons).¹¹

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.

Not Available

Food Interactions

No interactions found.

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Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Vtama	Cream	10 mg/1000mg	Topical	Dermavant Sciences, Inc.	2022-05-26	Not applicable

Categories

Drug Categories

• Aryl Hydrocarbon Receptor Agonist
• Benzene Derivatives
• Benzylidene Compounds
• Cytochrome P-450 CYP1A2 Substrates
• Cytochrome P-450 CYP2C19 Substrates
• Cytochrome P-450 CYP2C9 Substrates
• Cytochrome P-450 CYP2D6 Substrates
• Cytochrome P-450 CYP3A Substrates
• Cytochrome P-450 CYP3A4 Substrates
• Cytochrome P-450 Substrates
• Phenols

Chemical TaxonomyProvided by Classyfire

Description

This compound belongs to the class of organic compounds known as stilbenes. These are organic compounds containing a 1,2-diphenylethylene moiety. Stilbenes (C6-C2-C6 ) are derived from the common phenylpropene (C6-C3) skeleton building block. The introduction of one or more hydroxyl groups to a phenyl ring lead to stilbenoids.

Kingdom

Organic compounds

Super Class

Phenylpropanoids and polyketides

Class

Stilbenes

Sub Class

Not Available

Direct Parent

Stilbenes

Alternative Parents

Monocyclic monoterpenoids / Aromatic monoterpenoids / Phenylpropanes / Cumenes / Styrenes / Resorcinols / 1-hydroxy-4-unsubstituted benzenoids / 1-hydroxy-2-unsubstituted benzenoids / Organooxygen compounds / Hydrocarbon derivatives

Substituents

1-hydroxy-2-unsubstituted benzenoid / 1-hydroxy-4-unsubstituted benzenoid / Aromatic homomonocyclic compound / Aromatic monoterpenoid / Benzenoid / Cumene / Hydrocarbon derivative / Monocyclic benzene moiety / Monocyclic monoterpenoid / Monoterpenoid

Molecular Framework

Aromatic homomonocyclic compounds

External Descriptors

Not Available

Affected organisms

Not Available

Chemical Identifiers

UNII

84HW7D0V04

CAS number

79338-84-4

InChI Key

ZISJNXNHJRQYJO-CMDGGOBGSA-N

InChI

InChI=1S/C17H18O2/c1-12(2)17-15(18)10-14(11-16(17)19)9-8-13-6-4-3-5-7-13/h3-12,18-19H,1-2H3/b9-8+

IUPAC Name

5-[(E)-2-phenylethenyl]-2-(propan-2-yl)benzene-1,3-diol

SMILES

CC(C)C1=C(O)C=C(\C=C\C2=CC=CC=C2)C=C1O

References

General References

1. Joyce SA, Brachmann AO, Glazer I, Lango L, Schwar G, Clarke DJ, Bode HB: Bacterial biosynthesis of a multipotent stilbene. Angew Chem Int Ed Engl. 2008;47(10):1942-5. doi: 10.1002/anie.200705148. [Article]
2. Hu K, Webster JM: Antibiotic production in relation to bacterial growth and nematode development in Photorhabdus--Heterorhabditis infected Galleria mellonella larvae. FEMS Microbiol Lett. 2000 Aug 15;189(2):219-23. [Article]
3. Bissonnette R, Vasist LS, Bullman JN, Collingwood T, Chen G, Maeda-Chubachi T: Systemic Pharmacokinetics, Safety, and Preliminary Efficacy of Topical AhR Agonist Tapinarof: Results of a Phase 1 Study. Clin Pharmacol Drug Dev. 2018 Jun;7(5):524-531. doi: 10.1002/cpdd.439. Epub 2018 Feb 1. [Article]
4. Furue M, Hashimoto-Hachiya A, Tsuji G: Aryl Hydrocarbon Receptor in Atopic Dermatitis and Psoriasis. Int J Mol Sci. 2019 Oct 31;20(21). pii: ijms20215424. doi: 10.3390/ijms20215424. [Article]
5. Kennedy LH, Sutter CH, Leon Carrion S, Tran QT, Bodreddigari S, Kensicki E, Mohney RP, Sutter TR: 2,3,7,8-Tetrachlorodibenzo-p-dioxin-mediated production of reactive oxygen species is an essential step in the mechanism of action to accelerate human keratinocyte differentiation. Toxicol Sci. 2013 Mar;132(1):235-49. doi: 10.1093/toxsci/kfs325. Epub 2012 Nov 14. [Article]
6. Smith SH, Jayawickreme C, Rickard DJ, Nicodeme E, Bui T, Simmons C, Coquery CM, Neil J, Pryor WM, Mayhew D, Rajpal DK, Creech K, Furst S, Lee J, Wu D, Rastinejad F, Willson TM, Viviani F, Morris DC, Moore JT, Cote-Sierra J: Tapinarof Is a Natural AhR Agonist that Resolves Skin Inflammation in Mice and Humans. J Invest Dermatol. 2017 Oct;137(10):2110-2119. doi: 10.1016/j.jid.2017.05.004. Epub 2017 Jun 6. [Article]
7. Bissonnette R, Stein Gold L, Rubenstein DS, Tallman AM, Armstrong A: Tapinarof in the treatment of psoriasis: A review of the unique mechanism of action of a novel therapeutic aryl hydrocarbon receptor-modulating agent. J Am Acad Dermatol. 2021 Apr;84(4):1059-1067. doi: 10.1016/j.jaad.2020.10.085. Epub 2020 Nov 3. [Article]
8. Nakahara T, Mitoma C, Hashimoto-Hachiya A, Takahara M, Tsuji G, Uchi H, Yan X, Hachisuka J, Chiba T, Esaki H, Kido-Nakahara M, Furue M: Antioxidant Opuntia ficus-indica Extract Activates AHR-NRF2 Signaling and Upregulates Filaggrin and Loricrin Expression in Human Keratinocytes. J Med Food. 2015 Oct;18(10):1143-9. doi: 10.1089/jmf.2014.3396. Epub 2015 May 18. [Article]
9. Korn T, Bettelli E, Oukka M, Kuchroo VK: IL-17 and Th17 Cells. Annu Rev Immunol. 2009;27:485-517. doi: 10.1146/annurev.immunol.021908.132710. [Article]
10. Fernandez-Gallego N, Sanchez-Madrid F, Cibrian D: Role of AHR Ligands in Skin Homeostasis and Cutaneous Inflammation. Cells. 2021 Nov 15;10(11). pii: cells10113176. doi: 10.3390/cells10113176. [Article]
11. FDA Approved Drug Proucts: VTAMA (tapinarof) cream, for topical use [Link]

External Links

ChemSpider

4943924

RxNav

2602286

ChEMBL

CHEMBL259571

ZINC

ZINC000005761533

Wikipedia

Tapinarof

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Completed	Treatment	Psoriasis	3
4	Recruiting	Treatment	Psoriasis	1
3	Completed	Treatment	Atopic Dermatitis	3
3	Completed	Treatment	Psoriasis Vulgaris (Plaque Psoriasis)	3
3	Recruiting	Treatment	Atopic Dermatitis	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Cream	Topical	10 mg/1000mg

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US10426743	No	2019-10-01	2036-05-19
US10195160	No	2019-02-05	2036-05-19
US10647649	No	2020-05-12	2038-11-13
US11458108	No	2016-05-19	2036-05-19
US11597692	No	2018-11-13	2038-11-13
US11590088	No	2019-11-13	2039-11-13
US11612573	No	2016-05-19	2036-05-19
US11617724	No	2016-05-19	2036-05-19
US11622945	No	2016-05-19	2036-05-19

Properties

State

Solid

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
Water Solubility	0.0339 mg/mL	ALOGPS
logP	4.25	ALOGPS
logP	4.95	Chemaxon
logS	-3.9	ALOGPS
pKa (Strongest Acidic)	9.19	Chemaxon
pKa (Strongest Basic)	-5.9	Chemaxon
Physiological Charge	0	Chemaxon
Hydrogen Acceptor Count	2	Chemaxon
Hydrogen Donor Count	2	Chemaxon
Polar Surface Area	40.46 Å2	Chemaxon
Rotatable Bond Count	3	Chemaxon
Refractivity	79.67 m3·mol-1	Chemaxon
Polarizability	29.58 Å3	Chemaxon
Number of Rings	2	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	splash10-0f7c-2390000000-592f88b3e3063bc46373
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0a4i-0090000000-240b846e70eb7ac6bdaf
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0udi-0090000000-8c0b5fef049bcb2db1a5
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0udr-0090000000-a452e4c8fde64dc5319d
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	splash10-052k-0490000000-e68f71b73291ef999683
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0a4i-1970000000-347fc9c696dedb30e470
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	splash10-004i-0930000000-d721eae6c80848e4a8f8
Predicted 1H NMR Spectrum	1D NMR	Not Applicable
Predicted 13C NMR Spectrum	1D NMR	Not Applicable

Chromatographic Properties

Collision Cross Sections (CCS)

Adduct	CCS Value (Å2)	Source type	Source
[M-H]-	179.0776187	predicted	DarkChem Lite v0.1.0
[M-H]-	161.2049	predicted	DeepCCS 1.0 (2019)
[M+H]+	182.2976187	predicted	DarkChem Lite v0.1.0
[M+H]+	163.5629	predicted	DeepCCS 1.0 (2019)
[M+Na]+	180.2896187	predicted	DarkChem Lite v0.1.0
[M+Na]+	169.65605	predicted	DeepCCS 1.0 (2019)

Targets

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Details1. Aryl hydrocarbon receptor

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Agonist

General Function

Transcription regulatory region dna binding

Specific Function

Ligand-activated transcriptional activator. Binds to the XRE promoter region of genes it activates. Activates the expression of multiple phase I and II xenobiotic chemical metabolizing enzyme genes...

Gene Name

AHR

Uniprot ID

P35869

Uniprot Name

Aryl hydrocarbon receptor

Molecular Weight

96146.705 Da

References

1. FDA Approved Drug Proucts: VTAMA (tapinarof) cream, for topical use [Link]

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Drug created at November 18, 2007 18:29 / Updated at March 22, 2023 02:02