Clascoterone

Identification

Summary

Clascoterone is an androgen receptor antagonist used for the topical treatment of acne vulgaris in patients 12 years of age and older.

Brand Names

Winlevi

Generic Name

Clascoterone

DrugBank Accession Number

DB12499

Background

Clascoterone (cortexolone 17α-propionate, CB-03-01) is a novel antagonist of androgen receptors. It binds to androgen receptors with high affinity.³ By competing with androgens for binding to androgen receptors, clascoterone works by blocking the androgen receptor signalling cascades that promote acne pathogenesis, such as sebaceous gland proliferation, excess sebum production, and inflammatory pathways.⁵ In August 2020, FDA approved clascoterone for the first-in-class topical treatment of acne (acne vulgaris) in male and female patients 12 years and older.⁹ Clascoterone is also being investigated as a novel treatment for androgenetic alopecia.²

Type

Small Molecule

Groups

Approved, Investigational

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Clascoterone (DB12499)

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Weight

Average: 402.531
Monoisotopic: 402.240624195

Chemical Formula

C₂₄H₃₄O₅

Synonyms

• 11-deoxycortisol 17α-propionate
• Clascoterone
• Cortexolone 17alpha-propionate
• Cortexolone 17α-propionate

External IDs

• CB-03-01

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Pharmacology

Indication

Clascoterone is indicated for the topical treatment of acne vulgaris in patients 12 years of age and older.^10,11

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Treatment of	Acne vulgaris		••••••••••••	••••••••••• •••••		•••••

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Pharmacodynamics

Clascoterone exerts anti-androgenic effects by working as an antagonist at androgen receptors (ARs) expressed throughout the skin, including sebaceous glands, sebocytes, and dermal papilla cells.¹ Clascoterone blocks the effects of testosterone and dihydrotestosterone (DHT), which are androgens that bind to the ARs and contribute to the development of androgen-dependent conditions such as acne and alopecia.¹ In vitro, the antiandrogenic effects of clascoterone in human primary sebocytes occurred in a dose-dependent manner.³ Clascoterone mediates selective topical activity by mainly targeting androgen receptors at the site of application. It has limited systemic effects.¹

In clinical trials, HPA axis suppression was observed as a 30-minute post-stimulation serum cortisol level of ≤18 mcg/dL in 5% of adult subjects and 9% of adolescent subjects with acne vulgaris following two weeks of topical treatment of clascoterone. HPA axis function returned to normal following the discontinuation of drug treatment.¹⁰

Mechanism of action

Acne is a multifactorial skin condition characterized by excess sebum production, epithelial hyperkeratinization, proliferation of the skin commensal bacteria, and inflammation.^1,3 Circulating and locally synthesized natural ligands, testosterone and dihydrotestosterone (DHT), serve as causative factors in both males and females. Upon binding of DHT, the DHT-androgen receptor complex dimerizes and translocates to the nucleus where it promotes the transcription of genes involved in acne pathogenesis, including proliferation and differentiation of sebocytes, excess sebum production, and inflammatory cytokine production.³ Clascoterone is a potent antagonist at ARs and competes for androgens in binding to the receptor, thereby inhibiting downstream signalling of ARs that promote acne.¹

Androgenetic alopecia is also an androgen-dependent and highly genetic condition. Dihydrotestosterone (DHT) binds to ARs expressed on dermal papilla cells (DPC) in the scalp to induce AR-mediated transcription of genes that contribute to androgenic alopecia. By blocking the interaction between DHT and aARs, clascoterone inhibits AR-regulated transcription and DHT-induced IL-6 synthesis.²

Target	Actions	Organism
AAndrogen receptor	antagonist	Humans

Absorption

Upon topical application, clascoteronet permeates the skin to the dermal levels with minimal systemic absorption.⁴ In clinical trials, adult subjects with moderate to severe facial acne vulgaris received twice-daily topical application of six grams of clascoterone. The steady-state concentrations of the drug were reached within five days. Following two weeks, the mean ± SD Cmax was 4.5 ± 2.9 ng/mL and the mean ± SD area under the plasma concentration-time over the dosing interval (AUCꞇ) was 37.1 ± 22.3 h*ng/mL. The mean ± SD average plasma concentration (Cavg) was 3.1 ± 1.9 ng/mL.¹⁰

Volume of distribution

There is no information available on the volume of distribution.

Protein binding

Clascoterone is 84% to 89% bound to plasma proteins in vitro, regardless of drug concentrations.¹⁰

Metabolism

According to in vitro and clinical studies, the main possible primary metabolite of clascoterone is cortexolone, which is an inactive metabolite. The plasma concentrations of cortexolone were generally below or near the lower limit of quantitation (0.5 ng/mL).¹⁰ Although clascoterone penetrates the skin, the systemic activity of the drug is limited due to rapid hydrolysis of clascoterone into the inactive metabolite by skin and plasma esterases,^1,5,8 namely carboxylesterase.⁶

Hover over products below to view reaction partners

• Clascoterone
  • Cortexolone
  • Cortexolone 21-propionate

Route of elimination

Excretion of clascoterone has not been fully characterized in humans.¹⁰ Upon topical application, clascoterone is quickly hydrolyzed in the epidermis.¹

Half-life

There is limited information on the half life of clascoterone.¹⁰

Clearance

There is limited information on clearance of clascoterone.¹⁰

Adverse Effects

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Toxicity

There is no information available on the toxicity profile of clascoterone, such as LD₅₀ and overdose in humans.

Pathways

Not Available

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Not Available

Interactions

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This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Flotufolastat F-18	Clascoterone may decrease effectiveness of Flotufolastat F-18 as a diagnostic agent.

Food Interactions

No interactions found.

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International/Other Brands

Breezula / Winlevi

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Winlevi	Cream	1 % w/w	Topical	Sun Pharmaceutical Industries Limited	2023-09-08	Not applicable
Winlevi	Cream	1 g/100g	Topical	Sun Pharmaceutical Industries, Inc.	2021-10-04	Not applicable

Categories

ATC Codes

D10AX06 — Clascoterone

• D10AX — Other anti-acne preparations for topical use
• D10A — ANTI-ACNE PREPARATIONS FOR TOPICAL USE
• D10 — ANTI-ACNE PREPARATIONS
• D — DERMATOLOGICALS

Drug Categories

• 17-Hydroxycorticosteroids
• Acids, Acyclic
• Adrenal Cortex Hormones
• Androgen Receptor Antagonists
• Androgen Receptor Inhibitors
• Anti-Acne Preparations
• Anti-Acne Preparations for Topical Use
• Antiandrogens
• Cytochrome P-450 CYP1A2 Inhibitors
• Cytochrome P-450 CYP1A2 Inhibitors (weak)
• Cytochrome P-450 CYP2B6 Inhibitors
• Cytochrome P-450 CYP2B6 Inhibitors (weak)
• Cytochrome P-450 CYP2C19 Inhibitors
• Cytochrome P-450 CYP2C19 Inhibitors (weak)
• Cytochrome P-450 CYP2C8 Inhibitors
• Cytochrome P-450 CYP2C8 Inhibitors (weak)
• Cytochrome P-450 CYP2C9 Inhibitors
• Cytochrome P-450 CYP2C9 Inhibitors (weak)
• Cytochrome P-450 CYP2D6 Inhibitors
• Cytochrome P-450 CYP2D6 Inhibitors (weak)
• Cytochrome P-450 CYP2E1 Inhibitors
• Cytochrome P-450 CYP2E1 Inhibitors (weak)
• Cytochrome P-450 CYP3A Inhibitors
• Cytochrome P-450 CYP3A4 Inhibitors
• Cytochrome P-450 CYP3A4 Inhibitors (weak)
• Cytochrome P-450 Enzyme Inhibitors
• Dermatologicals
• Fatty Acids
• Fatty Acids, Volatile
• Fused-Ring Compounds
• Hormones
• Hormones, Hormone Substitutes, and Hormone Antagonists
• Hydroxycorticosteroids
• Lipids
• Pregnanes
• Pregnenediones
• Pregnenes
• Steroids

Chemical TaxonomyProvided by Classyfire

Description

This compound belongs to the class of organic compounds known as 21-hydroxysteroids. These are steroids carrying a hydroxyl group at the 21-position of the steroid backbone.

Kingdom

Organic compounds

Super Class

Lipids and lipid-like molecules

Class

Steroids and steroid derivatives

Sub Class

Hydroxysteroids

Direct Parent

21-hydroxysteroids

Alternative Parents

Gluco/mineralocorticoids, progestogins and derivatives / Steroid esters / 20-oxosteroids / 3-oxo delta-4-steroids / Delta-4-steroids / Cyclohexenones / Alpha-acyloxy ketones / Alpha-hydroxy ketones / Carboxylic acid esters / Monocarboxylic acids and derivatives / Primary alcohols / Organic oxides / Hydrocarbon derivatives

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Substituents

20-oxosteroid / 21-hydroxysteroid / 3-oxo-delta-4-steroid / 3-oxosteroid / Alcohol / Aliphatic homopolycyclic compound / Alpha-acyloxy ketone / Alpha-hydroxy ketone / Carbonyl group / Carboxylic acid derivative / Carboxylic acid ester / Cyclic ketone / Cyclohexenone / Delta-4-steroid / Hydrocarbon derivative / Ketone / Monocarboxylic acid or derivatives / Organic oxide / Organic oxygen compound / Organooxygen compound / Oxosteroid / Pregnane-skeleton / Primary alcohol / Progestogin-skeleton / Steroid ester

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Molecular Framework

Aliphatic homopolycyclic compounds

External Descriptors

Not Available

Affected organisms

Not Available

Chemical Identifiers

UNII

XN7MM8XG2M

CAS number

19608-29-8

InChI Key

GPNHMOZDMYNCPO-PDUMRIMRSA-N

InChI

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

IUPAC Name

(1R,3aS,3bR,9aR,9bS,11aS)-1-(2-hydroxyacetyl)-9a,11a-dimethyl-7-oxo-1H,2H,3H,3aH,3bH,4H,5H,7H,8H,9H,9aH,9bH,10H,11H,11aH-cyclopenta[a]phenanthren-1-yl propanoate

SMILES

[H][C@@]12CC[C@](OC(=O)CC)(C(=O)CO)[C@@]1(C)CC[C@@]1([H])[C@@]2([H])CCC2=CC(=O)CC[C@]12C

References

General References

1. Hebert A, Thiboutot D, Stein Gold L, Cartwright M, Gerloni M, Fragasso E, Mazzetti A: Efficacy and Safety of Topical Clascoterone Cream, 1%, for Treatment in Patients With Facial Acne: Two Phase 3 Randomized Clinical Trials. JAMA Dermatol. 2020 Apr 22. pii: 2765025. doi: 10.1001/jamadermatol.2020.0465. [Article]
2. Rosette C, Rosette N, Mazzetti A, Moro L, Gerloni M: Cortexolone 17alpha-Propionate (Clascoterone) is an Androgen Receptor Antagonist in Dermal Papilla Cells In Vitro J Drugs Dermatol. 2019 Feb 1;18(2):197-201. [Article]
3. Rosette C, Agan FJ, Mazzetti A, Moro L, Gerloni M: Cortexolone 17alpha-propionate (Clascoterone) Is a Novel Androgen Receptor Antagonist that Inhibits Production of Lipids and Inflammatory Cytokines from Sebocytes In Vitro J Drugs Dermatol. 2019 May 1;18(5):412-418. [Article]
4. Mazzetti A, Moro L, Gerloni M, Cartwright M: Pharmacokinetic Profile, Safety, and Tolerability of Clascoterone (Cortexolone 17-alpha propionate, CB-03-01) Topical Cream, 1% in Subjects With Acne Vulgaris: An Open-Label Phase 2a Study J Drugs Dermatol. 2019 Jun 1;18(6):563. [Article]
5. Eichenfield L, Hebert A, Gold LS, Cartwright M, Fragasso E, Moro L, Mazzetti A: Open-label, long-term extension study to evaluate the safety of clascoterone (CB-03-01) cream, 1% twice daily, in patients with acne vulgaris. J Am Acad Dermatol. 2020 Aug;83(2):477-485. doi: 10.1016/j.jaad.2020.04.087. Epub 2020 Apr 26. [Article]
6. Pyo SM, Maibach HI: Skin Metabolism: Relevance of Skin Enzymes for Rational Drug Design. Skin Pharmacol Physiol. 2019;32(5):283-294. doi: 10.1159/000501732. Epub 2019 Jul 29. [Article]
7. Tokudome Y, Katayanagi M, Hashimoto F: Esterase Activity and Intracellular Localization in Reconstructed Human Epidermal Cultured Skin Models. Ann Dermatol. 2015 Jun;27(3):269-74. doi: 10.5021/ad.2015.27.3.269. Epub 2015 May 29. [Article]
8. Ferraboschi P, Legnani L, Celasco G, Moro L, Ragonesi L, Colombo D: A full conformational characterization of antiandrogen cortexolone-17α-propionate and related compounds through theoretical calculations and nuclear magnetic resonance spectroscopy MedChemComm. 2014 April 4;5:904-914. [Article]
9. Drugs.com: FDA Approves Winlevi [Link]
10. FDA Approved Drug Products: WINLEVI (clascoterone) cream, for topical use [Link]
11. Health Canada Approved Drug Products: WINLEVI (clascoterone) cream for topical use (June 2023) [Link]

External Links

Human Metabolome Database

HMDB0304870

PubChem Compound

11750009

PubChem Substance

347828732

ChemSpider

9924713

RxNav

2474340

ChEMBL

CHEMBL3590187

ZINC

ZINC000006716459

Wikipedia

Clascoterone

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">

Phase	Status	Purpose	Conditions	Count
3	Completed	Treatment	Acne Vulgaris	3
3	Recruiting	Treatment	Androgenetic Alopecia (AGA)	2
2	Completed	Treatment	Acne Vulgaris	3
2	Completed	Treatment	Androgenetic Alopecia (AGA)	1
1	Completed	Other	Healthy Subjects (HS)	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Cream	Topical	1 % w/w
Cream	Topical	1 g/100g

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US10159682	No	2018-12-25	2028-08-14
US8143240	No	2012-03-27	2023-01-12
US9486458	No	2016-11-08	2028-07-24
US8865690	No	2014-10-21	2022-07-24
US9433628	No	2016-09-06	2029-02-08
US9211295	No	2015-12-15	2022-07-24
US8785427	No	2014-07-22	2030-07-25
US11207332	No	2021-12-28	2028-11-20

Properties

State

Solid

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
Water Solubility	0.00753 mg/mL	ALOGPS
logP	4.1	ALOGPS
logP	3.73	Chemaxon
logS	-4.7	ALOGPS
pKa (Strongest Acidic)	13.78	Chemaxon
pKa (Strongest Basic)	-3.3	Chemaxon
Physiological Charge	0	Chemaxon
Hydrogen Acceptor Count	4	Chemaxon
Hydrogen Donor Count	1	Chemaxon
Polar Surface Area	80.67 Å2	Chemaxon
Rotatable Bond Count	5	Chemaxon
Refractivity	109.59 m3·mol-1	Chemaxon
Polarizability	44.86 Å3	Chemaxon
Number of Rings	4	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	Yes	Chemaxon
Ghose Filter	Yes	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	No	Chemaxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0udi-0019700000-2280fa15d327ca816ba8
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	splash10-03di-1019000000-c9c67631db8ba3e8814a
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0frb-0389200000-b9135bd7e78970dbe04f
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0abc-9010000000-8be5b8d407d068aef97b
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	splash10-05fr-9022000000-bafd40be5dafde0ed75f
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	splash10-01bc-1941100000-61560a6546758a18c96d
Predicted 1H NMR Spectrum	1D NMR	Not Applicable
Predicted 13C NMR Spectrum	1D NMR	Not Applicable

Chromatographic Properties

Collision Cross Sections (CCS)

Adduct	CCS Value (Å2)	Source type	Source
[M-H]-	209.3252577	predicted	DarkChem Lite v0.1.0
[M-H]-	188.31245	predicted	DeepCCS 1.0 (2019)
[M+H]+	209.9312577	predicted	DarkChem Lite v0.1.0
[M+H]+	190.70802	predicted	DeepCCS 1.0 (2019)
[M+Na]+	208.6771577	predicted	DarkChem Lite v0.1.0
[M+Na]+	196.62056	predicted	DeepCCS 1.0 (2019)

Targets

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Details1. Androgen receptor

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Antagonist

General Function

Zinc ion binding

Specific Function

Steroid hormone receptors are ligand-activated transcription factors that regulate eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Transcription ...

Gene Name

AR

Uniprot ID

P10275

Uniprot Name

Androgen receptor

Molecular Weight

98987.9 Da

References

1. Celasco G, Moro L, Bozzella R, Ferraboschi P, Bartorelli L, Quattrocchi C, Nicoletti F: Biological profile of cortexolone 17alpha-propionate (CB-03-01), a new topical and peripherally selective androgen antagonist. Arzneimittelforschung. 2004;54(12):881-6. doi: 10.1055/s-0031-1297043. [Article]
2. Rosette C, Rosette N, Mazzetti A, Moro L, Gerloni M: Cortexolone 17alpha-Propionate (Clascoterone) is an Androgen Receptor Antagonist in Dermal Papilla Cells In Vitro J Drugs Dermatol. 2019 Feb 1;18(2):197-201. [Article]
3. Rosette C, Agan FJ, Mazzetti A, Moro L, Gerloni M: Cortexolone 17alpha-propionate (Clascoterone) Is a Novel Androgen Receptor Antagonist that Inhibits Production of Lipids and Inflammatory Cytokines from Sebocytes In Vitro J Drugs Dermatol. 2019 May 1;18(5):412-418. [Article]

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Drug created at October 20, 2016 22:38 / Updated at June 27, 2023 01:10