Identification

Name
Etretinate
Accession Number
DB00926  (APRD00966)
Type
Small Molecule
Groups
Withdrawn
Description

Etretinate is a medication used to treat severe psoriasis. It is a synthetic aromatic retinoid. The mechanism of action of etretinate is still incompletely understood although, like retinoic acid, it is thought to interfere with the terminal differentiation of keratinocytes. It is thought to bind to the retinoic acid receptors. Etretinate is also believed to enhance the binding of cAMP to the regulatory RI subunit of cAMP dependent protein kinases. It was removed from the United States market in 1998 and the Canadian market in 1996 as a psoriasis medication, due to the high risk of birth defects. Etretinate is now used to treat T-cell lymphomas. It also appears to inhibit NADH oxidase activity.

Structure
Thumb
Synonyms
Not Available
External IDs
RO 10-9359 / RO-10-9359
International/Other Brands
Tegison / Tigason (Chugai Pharmaceutical)
Categories
UNII
65M2UDR9AG
CAS number
54350-48-0
Weight
Average: 354.4825
Monoisotopic: 354.219494826
Chemical Formula
C23H30O3
InChI Key
HQMNCQVAMBCHCO-DJRRULDNSA-N
InChI
InChI=1S/C23H30O3/c1-8-26-23(24)14-17(3)11-9-10-16(2)12-13-21-18(4)15-22(25-7)20(6)19(21)5/h9-15H,8H2,1-7H3/b11-9+,13-12+,16-10+,17-14+
IUPAC Name
ethyl 9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethylnona-2,4,6,8-tetraenoate
SMILES
CCOC(=O)C=C(C)C=CC=C(C)C=CC1=C(C)C(C)=C(OC)C=C1C

Pharmacology

Indication

For the treatment of severe psoriasis in adults.

Structured Indications
Not Available
Pharmacodynamics

The active metabolite responsible for etretinate's effects, acitretin, is a retinoid. Retinoids have a structure similar to vitamin A and are involved in the normal growth of skin cells. Acitretin works by inhibiting the excessive cell growth and keratinisation (process by which skin cells become thickened due to the deposition of a protein within them) seen in psoriasis. It therefore reduces the thickening of the skin, plaque formation and scaling.

Mechanism of action

The mechanism of action of the active metabolite, acitretin, is unknown, however it is believed to work by targeting specific receptors (retinoid receptors) in the skin which help normalize the growth cycle of skin cells.

TargetActionsOrganism
ARetinoic acid receptor alpha
agonist
Human
ARetinoic acid receptor RXR-alpha
agonist
Human
ARetinoic acid receptor beta
agonist
Human
ARetinoic acid receptor RXR-gamma
agonist
Human
ARetinoic acid receptor RXR-beta
agonist
Human
ARetinoic acid receptor gamma
agonist
Human
Absorption

Absorbed in the small intestine. Studies in normal volunteers indicate that the absorption of etretinate is greater in patients consuming whole milk or a high-fat diet than in patients in a fasting state.

Volume of distribution
Not Available
Protein binding

More than 99% bound to plasma proteins, predominantly lipoproteins, whereas its active metabolite, acetretin (etretin), is predominantly bound to albumin.

Metabolism

Extensively metabolized, with significant first-pass metabolism to the pharmacologically active acid form. Subsequent metabolism results in the inactive 13-cis acid form, chain-shortened breakdown products, and conjugates that are ultimately excreted.

Route of elimination
Not Available
Half life

In one study, the apparent terminal half-life of etretinate after 6 months of therapy was approximately 120 days. In another study of 47 patients who had undergone chronic therapy with etretinate, 5 patients had detectable serum drug concentrations (0.5 to 12 ng/mL) 2.1 to 2.9 years after therapy was completed.

Clearance
Not Available
Toxicity

Symptoms of overdose include headache and vertigo.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
  • Avoid alcohol completely up to 2 months after discontinuation.
  • Increases absorption, take with food.

References

Synthesis Reference

Bollag. W., Ruegg, R. and Ryser, G.; U.S.Patent 4,105,681; August 8,1978; assigned to Hoffmann-LaRoche, Inc. Bollag, W., Ruegg, R. and Ryser, G.; U.S. Patent 4,215,215; July 29, 1980; assigned to Hoffmann-La Roche, Inc.

General References
Not Available
External Links
KEGG Drug
D00316
PubChem Compound
3312
PubChem Substance
46504486
ChemSpider
4445538
ChEBI
4913
ChEMBL
CHEMBL464
PharmGKB
PA449554
Wikipedia
Etretinate
ATC Codes
D05BB01 — Etretinate

Clinical Trials

Clinical Trials
Not Available

Pharmacoeconomics

Manufacturers
  • Hoffmann la roche inc
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)104-105Bollag. W., Ruegg, R. and Ryser, G.; U.S.Patent 4,105,681; August 8,1978; assigned to Hoffmann-LaRoche, Inc. Bollag, W., Ruegg, R. and Ryser, G.; U.S. Patent 4,215,215; July 29, 1980; assigned to Hoffmann-La Roche, Inc.
logP6.5Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.000405 mg/mLALOGPS
logP6.32ALOGPS
logP6.32ChemAxon
logS-5.9ALOGPS
pKa (Strongest Basic)-4.8ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area35.53 Å2ChemAxon
Rotatable Bond Count8ChemAxon
Refractivity113.68 m3·mol-1ChemAxon
Polarizability42.98 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.541
Caco-2 permeable+0.8686
P-glycoprotein substrateNon-substrate0.5795
P-glycoprotein inhibitor IInhibitor0.5432
P-glycoprotein inhibitor IINon-inhibitor0.884
Renal organic cation transporterNon-inhibitor0.8439
CYP450 2C9 substrateNon-substrate0.8474
CYP450 2D6 substrateNon-substrate0.8222
CYP450 3A4 substrateSubstrate0.5411
CYP450 1A2 substrateInhibitor0.824
CYP450 2C9 inhibitorNon-inhibitor0.7544
CYP450 2D6 inhibitorNon-inhibitor0.9149
CYP450 2C19 inhibitorInhibitor0.5241
CYP450 3A4 inhibitorNon-inhibitor0.8499
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.8041
Ames testNon AMES toxic0.6898
CarcinogenicityNon-carcinogens0.7795
BiodegradationReady biodegradable0.8896
Rat acute toxicity1.8763 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9002
hERG inhibition (predictor II)Non-inhibitor0.9289
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

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

Taxonomy

Description
This compound belongs to the class of organic compounds known as retinoid esters. These are ester derivatives of retinoic acid. These are obtained by formal condensation of the hydroxy group of retinol with the carboxy group of any carboxylic acid.
Kingdom
Organic compounds
Super Class
Lipids and lipid-like molecules
Class
Prenol lipids
Sub Class
Retinoids
Direct Parent
Retinoid esters
Alternative Parents
Sesquiterpenoids / Styrenes / Phenoxy compounds / Methoxybenzenes / Anisoles / Fatty acid esters / Alkyl aryl ethers / Enoate esters / Monocarboxylic acids and derivatives / Organic oxides
show 2 more
Substituents
Retinoid ester / Sesquiterpenoid / Cyclofarsesane sesquiterpenoid / Phenoxy compound / Anisole / Methoxybenzene / Phenol ether / Styrene / Alkyl aryl ether / Fatty acid ester
show 15 more
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
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 expressi...
Gene Name
RARA
Uniprot ID
P10276
Uniprot Name
Retinoic acid receptor alpha
Molecular Weight
50770.805 Da
References
  1. Harnish DC, Barua AB, Soprano KJ, Soprano DR: Induction of beta-retinoic acid receptor mRNA by teratogenic doses of retinoids in murine fetuses. Differentiation. 1990 Nov;45(2):103-8. [PubMed:1965892]
  2. Saurat JH: Retinoids and psoriasis: novel issues in retinoid pharmacology and implications for psoriasis treatment. J Am Acad Dermatol. 1999 Sep;41(3 Pt 2):S2-6. [PubMed:10459139]
  3. Zitnik RJ, Kotloff RM, Latifpour J, Zheng T, Whiting NL, Schwalb J, Elias JA: Retinoic acid inhibition of IL-1-induced IL-6 production by human lung fibroblasts. J Immunol. 1994 Feb 1;152(3):1419-27. [PubMed:8301142]
  4. Orfanos CE, Zouboulis CC, Almond-Roesler B, Geilen CC: Current use and future potential role of retinoids in dermatology. Drugs. 1997 Mar;53(3):358-88. [PubMed:9074840]
  5. Billoni N, Gautier B, Mahe YF, Bernard BA: Expression of retinoid nuclear receptor superfamily members in human hair follicles and its implication in hair growth. Acta Derm Venereol. 1997 Sep;77(5):350-5. [PubMed:9298126]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
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 expressi...
Gene Name
RXRA
Uniprot ID
P19793
Uniprot Name
Retinoic acid receptor RXR-alpha
Molecular Weight
50810.835 Da
References
  1. Zitnik RJ, Kotloff RM, Latifpour J, Zheng T, Whiting NL, Schwalb J, Elias JA: Retinoic acid inhibition of IL-1-induced IL-6 production by human lung fibroblasts. J Immunol. 1994 Feb 1;152(3):1419-27. [PubMed:8301142]
  2. Orfanos CE, Zouboulis CC, Almond-Roesler B, Geilen CC: Current use and future potential role of retinoids in dermatology. Drugs. 1997 Mar;53(3):358-88. [PubMed:9074840]
  3. Billoni N, Gautier B, Mahe YF, Bernard BA: Expression of retinoid nuclear receptor superfamily members in human hair follicles and its implication in hair growth. Acta Derm Venereol. 1997 Sep;77(5):350-5. [PubMed:9298126]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
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 expressi...
Gene Name
RARB
Uniprot ID
P10826
Uniprot Name
Retinoic acid receptor beta
Molecular Weight
50488.63 Da
References
  1. Zitnik RJ, Kotloff RM, Latifpour J, Zheng T, Whiting NL, Schwalb J, Elias JA: Retinoic acid inhibition of IL-1-induced IL-6 production by human lung fibroblasts. J Immunol. 1994 Feb 1;152(3):1419-27. [PubMed:8301142]
  2. Billoni N, Gautier B, Mahe YF, Bernard BA: Expression of retinoid nuclear receptor superfamily members in human hair follicles and its implication in hair growth. Acta Derm Venereol. 1997 Sep;77(5):350-5. [PubMed:9298126]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
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 expressi...
Gene Name
RXRG
Uniprot ID
P48443
Uniprot Name
Retinoic acid receptor RXR-gamma
Molecular Weight
50870.72 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284]
  2. 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. [PubMed:17016423]
  3. Billoni N, Gautier B, Mahe YF, Bernard BA: Expression of retinoid nuclear receptor superfamily members in human hair follicles and its implication in hair growth. Acta Derm Venereol. 1997 Sep;77(5):350-5. [PubMed:9298126]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
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 expressi...
Gene Name
RXRB
Uniprot ID
P28702
Uniprot Name
Retinoic acid receptor RXR-beta
Molecular Weight
56921.38 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284]
  2. 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. [PubMed:17016423]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
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 expressi...
Gene Name
RARG
Uniprot ID
P13631
Uniprot Name
Retinoic acid receptor gamma
Molecular Weight
50341.405 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284]
  2. 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. [PubMed:17016423]
  3. 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. [PubMed:10592235]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Oxygen binding
Specific Function
Catalyzes the formation of aromatic C18 estrogens from C19 androgens.
Gene Name
CYP19A1
Uniprot ID
P11511
Uniprot Name
Aromatase
Molecular Weight
57882.48 Da
References
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Retinoic acid binding
Specific Function
Plays a key role in retinoic acid metabolism. Acts on retinoids, including all-trans-retinoic acid (RA) and its stereoisomer 9-cis-RA. Capable of both 4-hydroxylation and 18-hydroxylation. Responsi...
Gene Name
CYP26A1
Uniprot ID
O43174
Uniprot Name
Cytochrome P450 26A1
Molecular Weight
56198.11 Da
References
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]

Carriers

Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Transporter activity
Specific Function
Cytosolic CRABPs may regulate the access of retinoic acid to the nuclear retinoic acid receptors.
Gene Name
CRABP1
Uniprot ID
P29762
Uniprot Name
Cellular retinoic acid-binding protein 1
Molecular Weight
15565.45 Da
References
  1. Madani K, Bazzano G, Chou A: Evaluation of retinoids as inhibitors of [3H] all-trans retinoic acid binding to cellular retinoic acid-binding protein in rat skin and testes. Arch Dermatol Res. 1986;278(4):302-6. [PubMed:3017242]

Drug created on June 13, 2005 07:24 / Updated on December 01, 2017 14:36