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General Description:

Tapinarof, identified by CAS number 79338-84-4, is a notable compound with significant therapeutic applications. 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. 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. 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. Tapinarof received initial approval from the FDA in 2022.

Indications:

This drug is primarily indicated for: Tapinarof is indicated for the topical treatment of plaque psoriasis in adults. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Tapinarof undergoes metabolic processing primarily in: Tapinarof is metabolized in the liver by multiple pathways including oxidation, glucuronidation, and sulfation in vitro.CYP1A2 and CYP3A4 appears to be the major enzyme involved in the hepatic metabolism of tapinarof, while CYP2C9, CYP2C19, and CYP2D6 play a minor role. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Tapinarof are crucial for its therapeutic efficacy: 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. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Tapinarof is an important consideration for its dosing schedule: Due to the insufficient data about the elimination phase, the terminal half-life of tapinarof cannot be determined. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Tapinarof exhibits a strong affinity for binding with plasma proteins: Human plasma protein binding of tapinarof is approximately 99% in vitro. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Volume of Distribution:

Tapinarof is distributed throughout the body with a volume of distribution of: The Vss of tapinarof is estimated to be from 1270 to 1500 mL/kg. This metric indicates how extensively the drug permeates into body tissues.

Pharmacodynamics:

Tapinarof exerts its therapeutic effects through: The pharmacodynamics of tapinarof are unknown. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Tapinarof functions by: 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. Upon binding to its ligand, AhR heterodimerizes with AhR nuclear translocator (ARNT) to form a complex with a high affinity for DNA binding. The AhR-ligand/ARNT complex can then bind to the specific DNA recognition sites to transcribe AhR-responsive genes. 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. Dysregulation of AhR is one of the hallmarks of psoriasis, as psoriasis patients have a higher serum concentration of AhR compared to healthy individuals. Treatment of AhR ligands in vitro also results in a gene expression profile that is implicated in the pathogenesis of psoriasis. 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. Additionally, AhR activation also recruits persistent skin resident memory T cells, thus contributing to the chronicity of psoriasis. However, the specific binding of tapinarof to AhR modulates a unique set of genes that are dysregulated in psoriasis, distinctive from other AhR ligands. 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. It is currently unknown why AhR ligands like tapinarof can reduce psoriatic inflammations in one setting but upregulate inflammatory genes in another setting. It is possible that the anti-inflammatory effect of tapinarof as an AhR agonist might be due to Nrf2. 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. Therefore, it is hypothesized that the dual AhR/Nrf2 action of tapinarof is essential to the effect of tapinarof in treating psoriasis. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Tapinarof 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, classified under the direct parent group Stilbenes. This compound is a part of the Organic compounds, falling under the Phenylpropanoids and polyketides superclass, and categorized within the Stilbenes class, specifically within the None subclass.

Categories:

Tapinarof is categorized under the following therapeutic classes: 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. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.