This drug entry is a stub and has not been fully annotated. It is scheduled to be annotated soon.

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
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

Pharmacology

Indication

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

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Associated Conditions
Contraindications & Blackbox Warnings
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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

TargetActionsOrganism
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.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
VtamaCream10 mg/1000mgTopicalDermavant Sciences, Inc.2022-05-26Not applicableUS flag

Categories

Drug Categories
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]
ChemSpider
4943924
RxNav
2602286
ChEMBL
CHEMBL259571
ZINC
ZINC000005761533
Wikipedia
3,5-Dihydroxy-4-isopropyl-trans-stilbene

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4RecruitingTreatmentPsoriasis (PsO)1
3CompletedTreatmentPsoriasis Vulgaris (Plaque Psoriasis)3
3RecruitingTreatmentAtopic Dermatitis4
3RecruitingTreatmentPsoriasis Vulgaris (Plaque Psoriasis)1
3WithdrawnTreatmentPsoriasis (PsO)1
2CompletedTreatmentAtopic Dermatitis2
2CompletedTreatmentPsoriasis (PsO)2
2CompletedTreatmentPsoriasis Vulgaris (Plaque Psoriasis)1
2RecruitingTreatmentAtopic Dermatitis1
1CompletedBasic ScienceAtopic Dermatitis1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
CreamTopical10 mg/1000mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0339 mg/mLALOGPS
logP4.25ALOGPS
logP4.95ChemAxon
logS-3.9ALOGPS
pKa (Strongest Acidic)9.19ChemAxon
pKa (Strongest Basic)-5.9ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area40.46 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity79.67 m3·mol-1ChemAxon
Polarizability29.58 Å3ChemAxon
Number of Rings2ChemAxon
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

Targets

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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]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
References
  1. 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]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. 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]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. 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]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55930.545 Da
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
References
  1. 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]

Drug created at November 18, 2007 18:29 / Updated at June 27, 2022 18:22