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
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.

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.

[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.

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。