The primary target of Trifarotene is the retinoic acid receptor gamma (RARγ). It acts as a potent and selective agonist, binding to RARγ and activating its transcriptional activity. This leads to the regulation of gene expression involved in cell differentiation, proliferation, and inflammation. The selective activation of RARγ is thought to contribute to its efficacy in treating acne with a favorable side-effect profile.

In remodeling human skin (RHE), trifarotene (CD5789) (3.3 μL 0.33 cm2; 24 hours) is involved in keratinization, desquamation, epidermalization, and cellular labeling. The average EC50 of all combined target genes for trifarotene is 0.0048% [2].
In vitro, trifarotene has been shown to be a potent agonist of RARγ with high selectivity over RARα and RARβ. It regulates the expression of genes involved in keratinocyte differentiation and inflammation. In cell-based assays, trifarotene reduces the production of inflammatory mediators and promotes the normalization of follicular epithelial differentiation.

It has been demonstrated that trifarotene (0.001%-0.01% in cream, 25 mg per mouse) is completely efficacious (98% decrease) when administered at 0.01% in comedogenic dosages [2].
In vivo, trifarotene is effective in reducing inflammatory and non-inflammatory lesions in patients with acne vulgaris. It is applied topically once daily and is generally well-tolerated. The compound has also shown efficacy in the treatment of ichthyosis. Trifarotene is the first RARγ-selective retinoid approved for the treatment of acne.

In vitro enzyme or receptor binding (non-cell) assays for trifarotene involve studying its binding affinity for the RARγ receptor. Radioligand binding assays are performed using purified RARγ receptor or cell lysates expressing the receptor. The compound is incubated with a radiolabeled ligand, and the displacement of the ligand is measured to determine the affinity. Selectivity is assessed by testing the compound against RARα and RARβ.

In vitro cell-based assays for trifarotene are performed using keratinocytes and other skin cells. Cells are treated with the compound, and the expression of RARγ target genes is measured by qPCR. The compound's effects on cell differentiation, proliferation, and inflammation are assessed. These assays confirm the compound's mechanism of action as a RARγ agonist.

Animal/Disease Models: Rhino mouse[2]
Doses: 0.001%, 0.0025%, 0.005% and 0.01% cream, the dose is 25 mg/mouse (5 cm2 surface of back skin, calculated as 5 mg/cm2) one time/day; 11 days
Experimental Results: Epidermal thickness increased by 275% (66 μm) and transepidermal water loss (TEWL) increased by 285% (26 g/h/m2).
In vivo animal experiments for trifarotene are conducted using animal models of acne and skin inflammation. The compound is applied topically, and its effects on skin lesions, inflammation, and keratinocyte differentiation are assessed. These studies confirm the compound's efficacy as a topical retinoid.

Absorption, Distribution and Excretion
Trifaratine has minimal systemic absorption. In a pharmacokinetic study involving 19 subjects, systemic concentrations were quantifiable in only 7 subjects—steady-state Cmax values ranged from undetectable (<5 pg/mL) to 10 pg/mL, and AUC0-24h ranged from 75 to 104 pg·h/mL. Trifaratine is primarily excreted in feces. Metabolism/Metabolites Trifaratine is rapidly metabolized in human hepatocytes—its half-life in human keratinocytes is >24 hours, while its half-life in human liver microsomes is approximately 5 minutes. The metabolism of trifaratine is primarily catalyzed by CYP2C9, CYP3A4, and CYP2C8, with a relatively minor role for CYP2B6. Biological Half-Life The terminal half-life of trifaratine is typically between 2 and 9 hours.
Pharmacokinetic (PK) properties of trifarotene indicate that it is minimally absorbed through the skin after topical application. The compound has a molecular weight of 436.55 and a molecular formula of C29H32N2O2. It is a solid at room temperature. Systemic exposure is low due to minimal absorption. The compound is metabolized in the liver and excreted renally and biliary.

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
No studies have been conducted on the use of trafarotine during lactation. Due to low absorption rates after topical application, the risk to breastfeeding infants is low. Do not apply trafarotine cream directly to the nipple and areola, and ensure that the infant's skin does not come into direct contact with the applied medication.
◉ Effects on Breastfed Infants
No published information found as of the revision date.
◉ Effects on Lactation and Breast Milk
No published information found as of the revision date.

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Protein Binding
Trafarotine has a protein binding rate of 99.9% in plasma.
Toxicology (toxicology) data for trifarotene indicate that it is generally well-tolerated when used topically. Common side effects include skin irritation, redness, and dryness at the application site. The compound should be used with caution in patients with a history of hypersensitivity to retinoids.

[1]. Structure-based design of Trifarotene (CD5789), a potent and selective RARγ agonist for the treatment of acne. Bioorg Med Chem Lett. 2018 Jun 1;28(10):1736-1741.

[2]. Nonclinical and human pharmacology of the potent and selective topical retinoic acid receptor-γ agonist trifarotene. Br J Dermatol. 2018 Aug;179(2):442-456.

Trifarotine is a topical retinoic acid cream used to treat acne vulgaris, first approved for marketing in the United States in October 2019. Retinoic acid drugs are structurally and functionally similar to vitamin A, but newer generation retinoic acid drugs like trefarotine and adapalene have very low structural similarity to vitamin A, sharing only functional similarity. Trifarotine is considered the first representative of the "fourth generation" of retinoic acid drugs due to its unique selective activity—this selectivity appears to offer higher efficacy and fewer side effects compared to older, less selective retinoic acid drugs.
Trefarotine is a retinoic acid drug.
Trefarotine is a selective retinoic acid receptor γ (RARγ) agonist used to treat acne vulgaris. After topical application, trifarotine selectively binds to RARγ receptors, thereby altering the expression of certain genes involved in inflammation and cell differentiation.
Drug Indications

Trefarotine is indicated for the topical treatment of acne vulgaris in patients aged 9 years and older.
Treatment of Ichthyosis
Treatment of Acne

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Mechanism of Action
Trifaratine is a potent and selective agonist of retinoic acid receptor γ (RAR-γ). It exhibits significantly reduced activity against RAR-β and RAR-α (16-fold and 65-fold lower than RAR-γ, respectively) and no activity against retinoic acid X receptor (RXR). Retinoic acid receptor agonists induce receptor dimerization, resulting in receptor-ligand dimers that bind to specific DNA regulatory sequences (retinoic acid response elements, or RAREs) in the promoter regions of retinoid-related genes. The altered expression of downstream genes induced by binding to these regions is the primary mechanism by which trifaratine exerts its comedogenic, anti-inflammatory, and depigmenting effects. Similar to other retinoids, trifaratine affects the expression of multiple genes involved in retinoid metabolism, epidermal differentiation/proliferation, and epidermal stress responses. Furthermore, trifaratine appears to modulate retinol-mediated pathways involved in proteolysis, skin hydration, and cell adhesion—modulation of these additional pathways has not been observed with other retinols and may therefore be specific to trifaratine.

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Pharmacodynamics
Trifaratine exerts its effects by activating retinol receptors—receptors that function to alter DNA transcription, thereby downstream regulating the expression of various genes involved in acne pathogenesis. It may cause skin irritation and should not be applied to wounds, abrasions, or other damaged skin. Because trifaratine may cause photosensitivity, patients should be advised to avoid excessive sun exposure; if sun exposure cannot be avoided, sunscreen and/or protective clothing should be used.
Other information: Trifarotene is a topical RARγ-selective retinoid used for the treatment of acne vulgaris. It is also known as CD5789. The compound is the first RARγ-selective retinoid approved for the treatment of acne. Its CAS number is 895542-09-3.

C29H33NO4

459.586

459.24

895542-09-3

895542-09-3;

11518241

White to off-white solid powder

1.2±0.1 g/cm3

641.9±55.0 °C at 760 mmHg

245C

342.0±31.5 °C

0.0±2.0 mmHg at 25°C

1.599

6.27

2

5

8

34

647

0

MFBCDACCJCDGBA-UHFFFAOYSA-N

InChI=1S/C29H33NO4/c1-29(2,3)25-19-23(10-12-26(25)30-14-4-5-15-30)24-18-22(11-13-27(24)34-17-16-31)20-6-8-21(9-7-20)28(32)33/h6-13,18-19,31H,4-5,14-17H2,1-3H3,(H,32,33)

3''-(tert-butyl)-4'-(2-hydroxyethoxy)-4''-(pyrrolidin-1-yl)-[1,1'

CD5789 CD-5789 CD 5789

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~250 mg/mL (~543.97 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (4.53 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (4.53 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)