Tapinarof Chemical Properties

Melting point:

140 - 142°C

Boiling point:

431.8±20.0 °C(Predicted)

Density 

1.158

storage temp. 

2-8°C

solubility 

Chloroform (Slightly), Methanol (Slightly)

pka

9.86±0.15(Predicted)

form 

Solid

color 

Pale Brown to Light Brown

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+

InChIKey

ZISJNXNHJRQYJO-CMDGGOBGSA-N

SMILES

C1(O)=CC(/C=C/C2=CC=CC=C2)=CC(O)=C1C(C)C

Tapinarof Usage And Synthesis

Description

Tapinarof is a small molecule stilbene compound, with a chemical name of 3,5-Dihydroxy-4-isopropylstilbene,which was originally isolated from the metabolite of photorhabdus iuminescence, a soil nematode (Heterorhabditis sp.), and has been synthesized artificially.

Biological activity

Tapinarof(GSK2894512) is a natural agonist of aryl hydrocarbon receptor (AhR) that induces nuclear translocation of AhR in immortalized keratinocytes (HaCaT) with EC50 of 0.16 nM. Benvitimod induces apoptosis in CD4+ T cells in a dose-dependent manner with an IC50 value of 5.2 μM.

Uses

Clinically, tapinarof was first used in the treatment of psoriasis and atopic dermatitis. Clinical trials conducted abroad have shown that Benzenemod cream has good efficacy and safety on atopic dermatitis and psoriasis. In China, as a class 1.1 new drug, Benzenemod cream has undergone phase I-II clinical trials, and the results show that it has good efficacy and safety for plaque psoriasis.

Uses

Tapinarof (WBI-1001) is a natural aryl hydrocarbon receptor (AhR) agonist with an EC50 of 13 nM. Tapinarof resolves skin inflammation in mice[1].

Application

Tapinarof (trade name Vtama), also known as GSK2894512, was discovered by GlaxoSmithKline and licensed by Dermavant Sciences (a subsidiary of Riovant Sciences) in 2020. Tapinarof is a first-in-class, topical aryl hydrocarbon receptor (AhR) agonist approved for the treatment of plaque psoriasis in adults.

Biological Activity

Benvitimod (Tapinarof) is an aryl hydrocarbon receptor (AHR) immunomodulator th at inhibits skin inflammation and enhances skin barrier function. Benvitimod is a metabolite, similar to resveratrol, produced by bacterial symbionts of entomopathogenic nematodes. It induces downregulation of inflammatory cytokines such as IL-17A, IL-17F, IL-19, IL-22, IL-23, and IL-1. Benvitimod also induces the expression of skin barrier genes related to keratinocyte differentiation.

Clinical Use

Tapinarof is a novel small molecule topical therapeutic AhR ( aryl hydrocarbon receptor)-modulating agent that has been recently approved by the FDA for the topical treatment of plaque psoriasis in adults. Tapinarof 1% cream has shown to be effective and to have a favorable safety profile in the treatment of psoriatic patients[1]. It could decrease the expression of multiple essential cytokines involved in the pathological IL-23/IL-17/IL-22 axis and ameliorate IMQ-induced psoriatic dermatitis, inhibiting keratinocyte proliferation and abnormal differentiation. But tapinarof may have different effects on varied types of psoriasis[2]. Tapinarof can also specifically bind to and activate AHR leading to downregulation of TNF-α/IL-23/IL-17 and inhibition of IL-4/IL-13 mediated STAT6 activation, to achieve the purpose of treating nonulcerated necrobiosis lipoidica[3].

Synthesis

The synthesis of Tapinarof begins with the aldol condensation of cinnamaldehyde (14.1) and ketone 14.2 to produce α, β, γ, δ-unsaturated ketone 14.3. Cinnamaldehyde (14.1) was subjected to Michael addition of diethyl malonate to give ketone 14.4 in 62% yield. Hydrolysis of 14.4 gave the malonic acid derivative 14.5. Treatment of 14.5 with a base at elevated temperature induced decarboxylation of the malonic acid molecule. Subsequently, the methyl ester was formed under the mediation of acid, and then the cyclic diketone 14.6 was obtained through Claisen condensation reaction in 79% yield over three steps. Chlorination of 14.6 with 1,3-dichloro-5,5-dimethylhydantoin (DCDMH) gave the penultimate intermediate 14.7 as a mixture of diastereoisomers in 96% yield. Treatment of the cyclic chlorodiketone 14.7 with tetraethylammonium chloride gave Tapinarof 14 in 86% yield.

in vivo

Tapinarof acts through AhR to reduce inflammation in IMQ-treated mice. AhR-sufficient mice on a C57Bl/6 background exhibit a reduced clinical score after treatment with Tapinarof or 6-formylindolo(3,2-b)carbazole (FICZ). In contrast, AhR KO mice do not respond to the anti-inflammatory effects of Tapinarof. FICZ is used as a comparator in these studies and yields similar results, with dramatically reduced inflammatory responses in wild-type, but not AhR KO mice.

References

[1] Bissonnette R, et al. Tapinarof for psoriasis and atopic dermatitis: 15?years of clinical research. Journal of the European Academy of Dermatology and Venereology, 2023; 37: 1168-1174.
[2] Zhu X, et al. The opposite effect of tapinarof between IMQ and IL-23 induced psoriasis mouse models. Experimental Dermatology, 2023.
[3] Palomares S, et al. Nonulcerated Necrobiosis Lipoidica Successfully Treated with Tapinarof: A Case Report. Clinical, Cosmetic and Investigational Dermatology, 2023; 16: 1373-1376.

Tapinarof(79338-84-4)Related Product Information

• Emamectin
• Polypropylenglycol diglycidyl ether
• Cyfluthrin
• 1,2-Diphenylethylenediamine
• DICHLOFLUANID
• Pidotimod
• Semapimod
• CIVENTICHEM CV-4057
• BAF-312(SiponiMod)
• tasquinimod
• Tiprotimod
• APILIMOD
• Ozanimod
• Fingolimod hydrochloride
• Calcipotriene
• Retinoic acid
• Polystyrene
• Iguratimod