Androgen receptor

Clascoterone is a novel, very effective topical antiandrogen that might help treat acne vulgaris. Very well tolerated, clascoterone 1% cream outperformed placebo clinically in TLC (P = 0·0017), ILC (P = 0·0134), and ASI (P = 0·0090). more efficient than the control medication. Additionally, the solution improves all of the previously listed metrics by 50% faster.

Absorption, Distribution and Excretion
Following topical application, claspone penetrates into the dermis, with minimal systemic absorption. In clinical trials, adult subjects with moderate to severe acne vulgaris applied 6 g of claspone topically twice daily. Steady-state concentrations were reached within five days. After two weeks, the mean ± standard deviation (Cmax) was 4.5 ± 2.9 ng/mL, and the mean ± standard deviation (AUC) was 37.1 ± 22.3 h ng/mL. The mean ± standard deviation (Cavg) of the mean plasma concentration was 3.1 ± 1.9 ng/mL. The excretion of claspone in humans is not fully understood. Following topical application, claspone is rapidly hydrolyzed within the epidermis. Information regarding volume of distribution is currently unavailable. Information regarding claspone clearance is limited. Metabolism/Metabolites Based on in vitro and clinical studies, the major probable metabolite of claspone is corticosterone, an inactive metabolite. Plasma concentrations of corticosterone are typically below or near the lower limit of quantification (0.5 ng/mL). Although clavusone can penetrate the skin, its systemic activity is limited because it is rapidly hydrolyzed into inactive metabolites by skin and plasma esterases (especially carboxylesterases).

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Biological Half-Life
Information on the half-life of clavusone is limited.

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
There is currently no information on the clinical use of clavusone during lactation. However, due to its poor absorption through the skin and high protein binding rate (84% to 89%), the concentration in breast milk is likely very low and is not expected to have any adverse effects on breastfed infants. Avoid application to the nipple area and ensure that the infant's skin does not come into direct contact with the treated area.
◉ Effects on Breastfed Infants
As of the revision date, no relevant published information was found.
◉ Effects on Lactation and Breast Milk
As of the revision date, no relevant published information was found.

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Protein Binding
Clavusone binds to plasma proteins in vitro at a rate of 84% to 89%, regardless of drug concentration.

[1]. Cortexolone 17-propionate 1% cream, a new potent antiandrogen for topical treatment of acne vulgaris. A pilot randomized, double-blind comparative study vs. placebo and tretinoin 0.5% cream. Br J Dermatol. 2011 Jul;165(1):177-83.

[2]. Cortexolone 17α-propionate 1% cream, a new potent antiandrogen for topical treatment of acne vulgaris. A pilot randomized, double-blind comparative study vs. placebo and tretinoin 0·05% cream. Br J Dermatol. 2011 Jul;165(1):177-83.

[3]. Biological profile of cortexolone 17alpha-propionate (CB-03-01), a new topical and peripherally selective androgen antagonist. Arzneimittelforschung. 2004;54(12):881-6.

Clascoterone (17α-corticosterone propionate, CB-03-01) is a novel androgen receptor antagonist. It binds to androgen receptors with high affinity. Clascoterone competitively binds to androgen receptors, blocking androgen receptor signaling pathways that promote acne pathogenesis, such as sebaceous hyperplasia, excessive sebum secretion, and inflammation. In August 2020, the FDA approved Clascoterone for the treatment of acne vulgaris in males and females aged 12 years and older, becoming the first approved topical medication of its kind. Clascoterone is also currently being investigated as a novel treatment for androgenetic alopecia. Clascoterone is an androgen receptor inhibitor. The mechanism of action of Clascoterone is as an androgen receptor antagonist. Drug Indications Clascoterone is indicated for the topical treatment of acne vulgaris in patients aged 12 years and older. Mechanism of Action Acne is a multifactorial skin disease characterized by excessive sebum secretion, hyperkeratosis of the epithelium, proliferation of dermal commensal flora, and inflammation. Circulating and locally synthesized natural ligands testosterone and dihydrotestosterone (DHT) are pathogenic factors in acne in both men and women. Upon binding to the androgen receptor, the DHT-androgen receptor complex dimers and translocates to the cell nucleus, where it promotes the transcription of genes involved in acne pathogenesis, including sebaceous cell proliferation and differentiation, excessive sebum secretion, and the production of inflammatory cytokines. Clascodone is a potent androgen receptor (AR) antagonist that competitively binds to the receptor with androgens, thereby inhibiting downstream AR signaling that promotes acne. Androgenetic alopecia is also an androgen-dependent and highly hereditary disease. Dihydrotestosterone (DHT) binds to AR expressed on dermal papillary cells (DPCs) of the scalp, inducing AR-mediated gene transcription of genes associated with androgenetic alopecia. Clascodone inhibits AR-regulated transcription and DHT-induced IL-6 synthesis by blocking the interaction between DHT and the androgen receptor (aAR).

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Pharmacodynamics
Clascodone exerts its anti-androgenic effect by antagonizing androgen receptors (ARs) distributed throughout the skin, including sebaceous glands, sebaceous cells, and dermal papillary cells. Clascodone blocks the effects of testosterone and dihydrotestosterone (DHT), both of which bind to androgen receptors (ARs) and contribute to androgen-dependent diseases such as acne and alopecia. In vitro studies have shown that the anti-androgenic effect of clascodone on human primary sebaceous cells is dose-dependent. Clascodone exerts its selective local effect primarily by targeting androgen receptors at the site of administration, with limited systemic effects. In clinical trials, two weeks after topical treatment with clascodone, 5% of adult acne patients and 9% of adolescent acne patients experienced hypothalamic-pituitary-adrenal (HPA) axis suppression with serum cortisol levels ≤18 mcg/dL 30 minutes after stimulation. HPA axis function returned to normal after discontinuation of the drug.

C24H34O5

402.53

402.24

C, 71.61; H, 8.51; O, 19.87

19608-29-8

19608-29-8;152-58-9;

11750009

White to light yellow solid powder

1.2±0.1 g/cm3

538.9±50.0 °C at 760 mmHg

179.3±23.6 °C

0.0±3.3 mmHg at 25°C

1.555

3.76

1

5

5

29

769

6

O=C1CC[C@@]2(C)C(CC[C@]3([H])[C@]2([H])CC[C@@]4(C)[C@@]3([H])CC[C@@]4(C(CO)=O)OC(CC)=O)=C1

GPNHMOZDMYNCPO-PDUMRIMRSA-N

InChI=1S/C24H34O5/c1-4-21(28)29-24(20(27)14-25)12-9-19-17-6-5-15-13-16(26)7-10-22(15,2)18(17)8-11-23(19,24)3/h13,17-19,25H,4-12,14H2,1-3H3/t17-,18+,19+,22+,23+,24+/m1/s1

[(8R,9S,10R,13S,14S,17R)-17-(2-hydroxyacetyl)-10,13-dimethyl-3-oxo-2,6,7,8,9,11,12,14,15,16-decahydro-1H-cyclopenta[a]phenanthren-17-yl] propanoate

CB03-01; CB 03-01; Clascoterone; 19608-29-8; Cortexolone 17alpha-propionate; Winlevi; breezula; clascoterona; XN7MM8XG2M; CB-03-01

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 : ≥ 100 mg/mL (~248.43 mM)

Solubility in Formulation 1: ≥ 2.75 mg/mL (6.83 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 27.5 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: ≥ 2.75 mg/mL (6.83 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 27.5 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.75 mg/mL (6.83 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 27.5 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.)