T3DB: Adapalene

Identification Taxonomy Biological Properties Physical Properties Toxicity Profile Spectra Concentrations Links References Gene Regulation Targets (6)XML

Targets (6)

Record Information

Version

2.0

Creation Date

2014-09-11 02:04:16 UTC

Update Date

2014-12-24 20:26:54 UTC

Accession Number

T3D4673

Identification

Common Name

Adapalene

Class

Small Molecule

Description

Adapalene is a topical retinoid primarily used in the treatment of acne and is also used (off-label) to treat keratosis pilaris as well as other skin conditions. It is currently marketed by Galderma under the trade names Differin in some countries, and Adaferin in India.

Compound Type

Anti-Inflammatory Agent, Non-Steroidal
Dermatologic Agent
Drug
Ester
Ether
Metabolite
Organic Compound
Synthetic Compound

Chemical Structure

MOL SDF PDB SMILES InChI

Synonyms

Synonym
6-(3-(1-Adamantyl)-4-methoxyphenyl)-2-naphthoic acid
Adaferin
Adapaleno
Adapalenum
Differin
Differine

Chemical Formula

C₂₈H₂₈O₃

Average Molecular Mass

412.520 g/mol

Monoisotopic Mass

412.204 g/mol

CAS Registry Number

106685-40-9

IUPAC Name

6-[3-(adamantan-1-yl)-4-methoxyphenyl]naphthalene-2-carboxylic acid

Traditional Name

differin

SMILES

COC1=C(C=C(C=C1)C1=CC=C2C=C(C=CC2=C1)C(O)=O)C12CC3CC(CC(C3)C1)C2

InChI Identifier

InChI=1S/C28H28O3/c1-31-26-7-6-23(21-2-3-22-12-24(27(29)30)5-4-20(22)11-21)13-25(26)28-14-17-8-18(15-28)10-19(9-17)16-28/h2-7,11-13,17-19H,8-10,14-16H2,1H3,(H,29,30)

InChI Key

InChIKey=LZCDAPDGXCYOEH-UHFFFAOYSA-N

Chemical Taxonomy

Description

belongs to the class of organic compounds known as retinoids. These are oxygenated derivatives of 3,7-dimethyl-1-(2,6,6-trimethylcyclohex-1-enyl)nona-1,3,5,7-tetraene and derivatives thereof.

Kingdom

Organic compounds

Super Class

Lipids and lipid-like molecules

Class

Prenol lipids

Sub Class

Retinoids

Direct Parent

Retinoids

Alternative Parents

Substituents

Adapalene
Phenylnaphthalene
2-naphthalenecarboxylic acid
2-naphthalenecarboxylic acid or derivatives
Naphthalene
Phenoxy compound
Anisole
Methoxybenzene
Phenol ether
Alkyl aryl ether
Monocyclic benzene moiety
Benzenoid
Monocarboxylic acid or derivatives
Ether
Carboxylic acid
Carboxylic acid derivative
Hydrocarbon derivative
Organic oxygen compound
Organic oxide
Organooxygen compound
Aromatic homopolycyclic compound

Molecular Framework

Aromatic homopolycyclic compounds

External Descriptors

monocarboxylic acid (CHEBI:31174 )
adamantanes (CHEBI:31174 )

Biological Properties

Status

Detected and Not Quantified

Origin

Exogenous

Cellular Locations

Cytoplasm
Extracellular
Membrane

Biofluid Locations

Not Available

Tissue Locations

Not Available

Pathways

Not Available

Applications

Not Available

Biological Roles

Not Available

Chemical Roles

Not Available

Physical Properties

State

Solid

Appearance

White powder.

Experimental Properties

Property	Value
Melting Point	Not Available
Boiling Point	Not Available
Solubility	4.01e-06 g/L
LogP	8.6

Predicted Properties

Property	Value	Source
Water Solubility	4.0e-06 g/L	ALOGPS
logP	6.06	ALOGPS
logP	6.46	ChemAxon
logS	-8	ALOGPS
pKa (Strongest Acidic)	3.99	ChemAxon
pKa (Strongest Basic)	-4.8	ChemAxon
Physiological Charge	-1	ChemAxon
Hydrogen Acceptor Count	3	ChemAxon
Hydrogen Donor Count	1	ChemAxon
Polar Surface Area	46.53 Å²	ChemAxon
Rotatable Bond Count	4	ChemAxon
Refractivity	122.07 m³·mol⁻¹	ChemAxon
Polarizability	47.65 Å³	ChemAxon
Number of Rings	6	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	Yes	ChemAxon
Veber's Rule	Yes	ChemAxon
MDDR-like Rule	Yes	ChemAxon

Spectra

Spectrum Type	Description	Splash Key	Deposition Date	View
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	splash10-0002-0009000000-2169879160d27fbd36e2	2017-09-01	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (1 TMS) - 70eV, Positive	splash10-00xs-8006900000-dedd288878501d101021	2017-10-06	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	Not Available	2021-10-12	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Positive	splash10-03dj-0009500000-35bff807860c9c78b28c	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Positive	splash10-00kb-0119100000-2a0a0656abf4155b2552	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Positive	splash10-0uei-0309000000-7b9438a46b2f18cdc7df	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Negative	splash10-03di-0005900000-f70dd1ca3170a3828c5b	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Negative	splash10-0i00-0019300000-00ba903e8fb2abb8a386	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Negative	splash10-0ue9-1149000000-d93742cdc7563deb95fa	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Negative	splash10-014i-0009400000-dc3263730bd61e4428ca	2021-09-22	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Negative	splash10-014i-0009000000-981559d240019f5c2b78	2021-09-22	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Negative	splash10-114r-0229100000-28732127a9e20d3c667a	2021-09-22	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Positive	splash10-03di-0007900000-9ec13495747ce0352fb2	2021-09-22	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Positive	splash10-03dj-0409700000-93449856a5a1558c8801	2021-09-22	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Positive	splash10-000i-0693100000-58ea252b7486c8e5f288	2021-09-22	View Spectrum

Toxicity Profile

Route of Exposure

Absorption of adapalene through human skin is low. Only trace amounts (<0.25 ng/mL) of parent substance have been found in the plasma of acne patients following chronic topical application of adapalene in controlled clinical trials

Mechanism of Toxicity

Mechanistically, adapalene binds to specific retinoic acid nuclear receptors (gamma and beta) and retinoid X receptors but does not bind to the cytosolic receptor protein. Although the exact mode of action of adapalene is unknown, it is suggested that topical adapalene may normalize the differentiation of follicular epithelial cells resulting in decreased microcomedone formation.

Metabolism

Metabolized mainly by O-demethylation, hydroxylation and conjugation, and excretion is primarily by the biliary route. Route of Elimination: Excretion appears to be primarily by the biliary route.

Toxicity Values

The acute oral toxicity of adapalene in mice and rats is greater than 10 mL/kg

Lethal Dose

Not Available

Carcinogenicity (IARC Classification)

No indication of carcinogenicity to humans (not listed by IARC).

Uses/Sources

For the topical treatment of comedo, papular and pustular acne (acne vulgaris) of the face, chest or back.

Minimum Risk Level

Not Available

Health Effects

Chronic ingestion of the drug may lead to the same side effects as those associated with excessive oral intake of Vitamin A.

Symptoms

Not Available

Treatment

Not Available

Normal Concentrations

Not Available

Abnormal Concentrations

Not Available

External Links

DrugBank ID

HMDB ID

PubChem Compound ID

ChEMBL ID

ChemSpider ID

KEGG ID

Not Available

UniProt ID

Not Available

OMIM ID

ChEBI ID

31174

BioCyc ID

Not Available

CTD ID

Not Available

Stitch ID

Not Available

PDB ID

Not Available

ACToR ID

Not Available

Wikipedia Link

Adapalene

References

Synthesis Reference

Graziano Castaldi, Pietro Allegrini, Gabriele Razzetti, Mauro Ercoli, “Process for the preparation of adapalene.” U.S. Patent US20060229465, issued October 12, 2006.

MSDS

Link

General References

Rolewski SL: Clinical review: topical retinoids. Dermatol Nurs. 2003 Oct;15(5):447-50, 459-65. [14619325 ]

Gene Regulation

Up-Regulated Genes

Not Available

Down-Regulated Genes

Not Available

Targets

Target Details

1. Retinoic acid receptor alpha

General Function:: Zinc ion binding
Specific Function:: Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RXR/RAR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. In the absence of ligand, the RXR-RAR heterodimers associate with a multiprotein complex containing transcription corepressors that induce histone acetylation, chromatin condensation and transcriptional suppression. On ligand binding, the corepressors dissociate from the receptors and associate with the coactivators leading to transcriptional activation. RARA plays an essential role in the regulation of retinoic acid-induced germ cell development during spermatogenesis. Has a role in the survival of early spermatocytes at the beginning prophase of meiosis. In Sertoli cells, may promote the survival and development of early meiotic prophase spermatocytes. In concert with RARG, required for skeletal growth, matrix homeostasis and growth plate function (By similarity). Regulates expression of target genes in a ligand-dependent manner by recruiting chromatin complexes containing KMT2E/MLL5. Mediates retinoic acid-induced granulopoiesis.
Gene Name:: RARA
Uniprot ID:: P10276
Molecular Weight:: 50770.805 Da

References

Shroot B, Michel S: Pharmacology and chemistry of adapalene. J Am Acad Dermatol. 1997 Jun;36(6 Pt 2):S96-103. [9204085 ]
Griffiths CE, Ancian P, Humphries J, Poncet M, Rizova E, Michel S, Clucas A: Adapalene 0.1% gel and adapalene 0.1% cream stimulate retinoic acid receptor mediated gene transcription without significant irritative effects in the skin of healthy human volunteers. Br J Dermatol. 1998 Oct;139 Suppl 52:12-6. [9990415 ]
Michel S, Jomard A, Demarchez M: Pharmacology of adapalene. Br J Dermatol. 1998 Oct;139 Suppl 52:3-7. [9990413 ]
Shroot B, Michel S, Allec J, Chatelus A, Wagner N: A new concept of drug delivery for acne. Dermatology. 1998;196(1):165-70. [9557255 ]
Kim MJ, Ciletti N, Michel S, Reichert U, Rosenfield RL: The role of specific retinoid receptors in sebocyte growth and differentiation in culture. J Invest Dermatol. 2000 Feb;114(2):349-53. [10651997 ]

Target Details

2. Retinoic acid receptor beta

General Function:: Zinc ion binding
Specific Function:: Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RXR/RAR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. In the absence or presence of hormone ligand, acts mainly as an activator of gene expression due to weak binding to corepressors. In concert with RARG, required for skeletal growth, matrix homeostasis and growth plate function.
Gene Name:: RARB
Uniprot ID:: P10826
Molecular Weight:: 50488.63 Da

References

Shroot B, Michel S: Pharmacology and chemistry of adapalene. J Am Acad Dermatol. 1997 Jun;36(6 Pt 2):S96-103. [9204085 ]
Shroot B, Michel S, Allec J, Chatelus A, Wagner N: A new concept of drug delivery for acne. Dermatology. 1998;196(1):165-70. [9557255 ]
Michel S, Jomard A, Demarchez M: Pharmacology of adapalene. Br J Dermatol. 1998 Oct;139 Suppl 52:3-7. [9990413 ]
Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [11752352 ]

Target Details

3. Retinoic acid receptor RXR-beta

General Function:: Zinc ion binding
Specific Function:: Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RAR/RXR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5 (By similarity). Specifically binds 9-cis retinoic acid (9C-RA).
Gene Name:: RXRB
Uniprot ID:: P28702
Molecular Weight:: 56921.38 Da

References

Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [17139284 ]
Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [17016423 ]
Kim MJ, Ciletti N, Michel S, Reichert U, Rosenfield RL: The role of specific retinoid receptors in sebocyte growth and differentiation in culture. J Invest Dermatol. 2000 Feb;114(2):349-53. [10651997 ]

Target Details

4. Retinoic acid receptor RXR-gamma

General Function:: Zinc ion binding
Specific Function:: Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RAR/RXR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. The high affinity ligand for RXRs is 9-cis retinoic acid (By similarity).
Gene Name:: RXRG
Uniprot ID:: P48443
Molecular Weight:: 50870.72 Da

References

Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [17139284 ]
Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [17016423 ]
Kim MJ, Ciletti N, Michel S, Reichert U, Rosenfield RL: The role of specific retinoid receptors in sebocyte growth and differentiation in culture. J Invest Dermatol. 2000 Feb;114(2):349-53. [10651997 ]

Target Details

5. Retinoic acid receptor gamma

General Function:: Zinc ion binding
Specific Function:: Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RAR/RXR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. In the absence of ligand, acts mainly as an activator of gene expression due to weak binding to corepressors. Required for limb bud development. In concert with RARA or RARB, required for skeletal growth, matrix homeostasis and growth plate function (By similarity).
Gene Name:: RARG
Uniprot ID:: P13631
Molecular Weight:: 50341.405 Da

References

Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [17139284 ]
Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [17016423 ]
Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. [10592235 ]

Target Details

6. Retinoic acid receptor RXR-alpha

General Function:: Zinc ion binding
Specific Function:: Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RAR/RXR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. The high affinity ligand for RXRs is 9-cis retinoic acid. RXRA serves as a common heterodimeric partner for a number of nuclear receptors. The RXR/RAR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. In the absence of ligand, the RXR-RAR heterodimers associate with a multiprotein complex containing transcription corepressors that induce histone acetylation, chromatin condensation and transcriptional suppression. On ligand binding, the corepressors dissociate from the receptors and associate with the coactivators leading to transcriptional activation. The RXRA/PPARA heterodimer is required for PPARA transcriptional activity on fatty acid oxidation genes such as ACOX1 and the P450 system genes.
Gene Name:: RXRA
Uniprot ID:: P19793
Molecular Weight:: 50810.835 Da

References

Bernard BA: Adapalene, a new chemical entity with retinoid activity. Skin Pharmacol. 1993;6 Suppl 1:61-9. [8142113 ]
Kim MJ, Ciletti N, Michel S, Reichert U, Rosenfield RL: The role of specific retinoid receptors in sebocyte growth and differentiation in culture. J Invest Dermatol. 2000 Feb;114(2):349-53. [10651997 ]

Adapalene (T3D4673)

Structure for T3D4673: Adapalene

Targets

References

References

References

References

References

References