Identification

Name
Clascoterone
Accession Number
DB12499
Description

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
Thumb
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

Pharmacology

Indication

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

Associated Conditions
Contraindications & Blackbox Warnings
Learn about our commercial Contraindications & Blackbox Warnings data.
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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

TargetActionsOrganism
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

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
Learn about our commercial Adverse Effects data.
Learn More
Toxicity

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

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
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.
Not Available
Food Interactions
No interactions found.

Products

International/Other Brands
Breezula / Winlevi

Categories

Drug Categories
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
show 3 more
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
show 15 more
Molecular Framework
Aliphatic homopolycyclic compounds
External Descriptors
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][[email protected]@]12CC[[email protected]](OC(=O)CC)(C(=O)CO)[[email protected]@]1(C)CC[[email protected]@]1([H])[[email protected]@]2([H])CCC2=CC(=O)CC[[email protected]]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. [PubMed:32320027]
  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. [PubMed:30811143]
  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. [PubMed:31141847]
  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. [PubMed:31251549]
  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. [PubMed:32348828]
  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. [PubMed:31357203]
  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. [PubMed:26082583]
  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.
  9. Drugs.com: FDA Approves Winlevi [Link]
  10. FDA Approved Drug Products: WINLEVI (clascoterone) cream, for topical use [Link]
PubChem Compound
11750009
PubChem Substance
347828732
ChemSpider
9924713
ChEMBL
CHEMBL3590187
ZINC
ZINC000006716459
Wikipedia
Clascoterone

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedTreatmentAcne Vulgaris3
2CompletedTreatmentAcne Vulgaris3
2CompletedTreatmentAndrogenetic Alopecia1
1CompletedOtherHealthy Volunteers1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00753 mg/mLALOGPS
logP4.1ALOGPS
logP3.73ChemAxon
logS-4.7ALOGPS
pKa (Strongest Acidic)13.78ChemAxon
pKa (Strongest Basic)-3.3ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area80.67 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity109.59 m3·mol-1ChemAxon
Polarizability44.87 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Targets

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. [PubMed:15646372]
  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. [PubMed:30811143]
  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. [PubMed:31141847]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
Curator comments
Clascoterone inhibited this enzyme in vitro with an IC50 value of >40 µM.
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
References
  1. FDA Approved Drug Products: WINLEVI (clascoterone) cream, for topical use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
Curator comments
Clascoterone inhibited this enzyme in vitro with an IC50 value of >40 µM.
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2B6
Uniprot ID
P20813
Uniprot Name
Cytochrome P450 2B6
Molecular Weight
56277.81 Da
References
  1. FDA Approved Drug Products: WINLEVI (clascoterone) cream, for topical use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
Curator comments
Clascoterone inhibited this enzyme in vitro with an IC50 value of >40 µM.
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
References
  1. FDA Approved Drug Products: WINLEVI (clascoterone) cream, for topical use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
Curator comments
Clascoterone inhibited this enzyme in vitro with an IC50 value of >40 µM.
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. FDA Approved Drug Products: WINLEVI (clascoterone) cream, for topical use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
Curator comments
Clascoterone inhibited this enzyme in vitro with an IC50 value of >40 µM.
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55930.545 Da
References
  1. FDA Approved Drug Products: WINLEVI (clascoterone) cream, for topical use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
Curator comments
Clascoterone inhibited this enzyme in vitro with an IC50 value of >40 µM.
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
References
  1. FDA Approved Drug Products: WINLEVI (clascoterone) cream, for topical use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
Curator comments
Clascoterone inhibited this enzyme in vitro with an IC50 value of >40 µM.
General Function
Steroid hydroxylase activity
Specific Function
Metabolizes several precarcinogens, drugs, and solvents to reactive metabolites. Inactivates a number of drugs and xenobiotics and also bioactivates many xenobiotic substrates to their hepatotoxic ...
Gene Name
CYP2E1
Uniprot ID
P05181
Uniprot Name
Cytochrome P450 2E1
Molecular Weight
56848.42 Da
References
  1. FDA Approved Drug Products: WINLEVI (clascoterone) cream, for topical use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
Curator comments
Clascoterone inhibited this enzyme in vitro with an IC50 value of >40 µM.
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. FDA Approved Drug Products: WINLEVI (clascoterone) cream, for topical use [Link]

Drug created on October 20, 2016 16:38 / Updated on September 03, 2020 14:54

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