Trifarotene (CD5789)   中文名称: 曲法罗汀

在重塑人类皮肤 (RHE) 过程中，trifarotene (CD5789)（3.3 μL 0.33 cm2；24 小时）参与角化、脱屑、表皮化和细胞标记。 trifarotene 所有组合靶基因的平均 EC50 为 0.0048% [2]。

已经证明，当以 0.01% 的致粉刺剂量给药时，曲法罗汀（乳膏中 0.001%-0.01%，每只小鼠 25 毫克）完全有效（减少 98%）[2]。

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).

Absorption, Distribution and Excretion
Systemic absorption of trifarotene is minimal. In a pharmacokinetic study involving 19 subjects, systemic concentrations were only quantifiable in 7 - 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.
Trifarotene is eliminated primarily in the feces.

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Metabolism / Metabolites
Trifarotene is rapidly metabolized in human hepatocytes - its observed half-life in human keratinocytes is >24 hours, whereas half-life in human liver microsomes is approximately 5 minutes. Metabolism of trifarotene is catalyzed primarily by CYP2C9, CYP3A4, CYP2C8, and, to a lesser extent, CYP2B6.

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Biological Half-Life
The terminal half-life of trifarotene is typically between 2 to 9 hours.

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Trifarotene has not been studied during breastfeeding. Because it is poorly absorbed after topical application, it is a low risk to the nursing infant. Do not apply trifarotene cream directly to the nipple and areola and ensure that the infant's skin does not come into direct contact with the areas of skin that have been treated.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Trifarotene is 99.9% protein bound in plasma.

[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.

Trifarotene is a topical retinoid cream used in the treatment of acne vulgaris that was first approved for use in the United States in October 2019. Retinoids are a class of medications structurally and functionally analogous to [vitamin A], though later generation retinoids such as trifarotene and [adapalene] bear little structural resemblance to vitamin A and are analogous only in function. Trifarotene is considered the first of the "fourth-generation" retinoids due to its uniquely selective activity - this selectivity appears to confer improved efficacy and reduced side effects as compared to older, less selective retinoids.
Trifarotene is a Retinoid.
Trifarotene is a selective retinoic acid receptor gamma (RAR gamma) agonist that can be used in the treatment of acne vulgaris. Upon topical application, trifarotene selectively binds to the RAR gamma receptor, thereby altering the expression of certain genes that are involved in inflammation and cellular differentiation.

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Drug Indication
Trifarotene is indicated for the topical treatment of acne vulgaris in patients 9 years of age and older.
Treatment of ichthyoses
Treatment of acne

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Mechanism of Action
Trifarotene is a potent and selective agonist of retinoic acid receptor-γ (RAR-γ). It has significantly less activity at RAR-β and RAR-α (16- and 65-fold lower than activity at RAR-γ, respectively), and has no activity at retinoid X receptors (RXRs). Agonism at retinoic acid receptors results in dimerization, and the resulting receptor-ligand dimer binds to specific DNA regulatory sequences (retinoic acid response elements, or RAREs) in the promotor regions of retinoid-responsible genes. Downstream alterations to gene expression induced by binding to these regions is the principle mechanism through which trifarotene exerts its comedolytic, anti-inflammatory, and depigmenting effects. Like other retinoids, trifarotene influences the expression of a number of genes involved in retinoid metabolism, epidermal differentiation/proliferation, and epidermal response to stress. In addition, trifarotene appears to modulate retinoid-mediated pathways involved in proteolysis, skin hydration, and cell adhesion - modulation of these additional pathways has not been observed with other retinoids and may therefore be unique to trifarotene.

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Pharmacodynamics
Trifarotene exerts its effects via agonism at retinoid receptors - these receptors function to alter DNA transcription, resulting in downstream modulation of the expression of various genes involved in acne pathogenesis. It may be associated with skin irritation and should not be applied to cuts, abrasions, or otherwise damaged skin. As trifarotene may result in photosensitivity, patients should be cautioned to avoid excess sun exposure and to use sunscreen and/or protective clothing if exposure is unavoidable.

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

70

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)

配方 1 中的溶解度: ≥ 2.08 mg/mL (4.53 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 20.8 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.08 mg/mL (4.53 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。