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Identification
NameTrilostane
Accession NumberDB01108  (APRD01276)
TypeSmall Molecule
GroupsApproved, Investigational, Withdrawn
Description

Trilostane is an inhibitor of 3 beta-hydroxysteroid dehydrogenase used in the treatment of Cushing’s syndrome. It was withdrawn from the United States market in April 1994. [Wikipedia]

Structure
Thumb
Synonyms
SynonymLanguageCode
TrilostanoNot AvailableNot Available
TrilostanumNot AvailableNot Available
SaltsNot Available
Brand names
NameCompany
DesopanNot Available
ModrastaneNot Available
ModrenalNot Available
Brand mixturesNot Available
Categories
CAS number13647-35-3
WeightAverage: 329.4333
Monoisotopic: 329.199093735
Chemical FormulaC20H27NO3
InChI KeyKVJXBPDAXMEYOA-CXANFOAXSA-N
InChI
InChI=1S/C20H27NO3/c1-18-7-6-14-12(13(18)3-4-15(18)22)5-8-20-17(24-20)16(23)11(10-21)9-19(14,20)2/h12-15,17,22-23H,3-9H2,1-2H3/t12-,13-,14-,15-,17+,18-,19+,20+/m0/s1
IUPAC Name
(1S,2R,6R,8S,11S,12S,15S,16S)-5,15-dihydroxy-2,16-dimethyl-7-oxapentacyclo[9.7.0.0^{2,8}.0^{6,8}.0^{12,16}]octadec-4-ene-4-carbonitrile
SMILES
[H][C@]12O[C@]11CC[C@@]3([H])[C@]4([H])CC[C@H](O)[C@@]4(C)CC[C@]3([H])[C@@]1(C)CC(C#N)=C2O
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassLipids
ClassSteroids and Steroid Derivatives
SubclassAndrogens and Derivatives
Direct parentAndrogens and Derivatives
Alternative parentsSecondary Alcohols; Cyclic Alcohols and Derivatives; Nitriles; Polyamines; Epoxides; Enols; Ethers
Substituentscyclic alcohol; secondary alcohol; carbonitrile; polyamine; enol; nitrile; oxirane; ether; alcohol; organonitrogen compound
Classification descriptionThis compound belongs to the androgens and derivatives. These are hydroxylated C19 steroid hormones. They are known to favour the development of masculine characteristics. They also show profound effects on scalp and body hair in humans.
Pharmacology
IndicationUsed in the treatment of Cushing's syndrome. It is normally used in short-term treatment until permanent therapy is possible.
PharmacodynamicsTrilostane blocks an enzyme involved in the production of several steroids including cortisol. Inhibiting this enzyme inhibits the production of cortisol. In Cushing's syndrome, the adrenal gland overproduces steroids. Although steroids are important for various functions of the body, too much can cause problems. Trilostane reduces the amount of steroids produced by the adrenal gland. This product was withdrawn from the U.S. market in April 1994.
Mechanism of actionTrilostane produces suppression of the adrenal cortex by inhibiting enzymatic conversion of steroids by 3-beta-hydroxysteroid dehydrogenase/delta 5,4 ketosteroid isomerase, thus blocking synthesis of adrenal steroids.
AbsorptionNot Available
Volume of distributionNot Available
Protein bindingNot Available
Metabolism

Hepatic.

Route of eliminationNot Available
Half life8 hours.
ClearanceNot Available
ToxicitySymptoms of overdose include darkening of skin, drowsiness or tiredness, loss of appetite, mental depression, skin rash, and/or vomiting.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9935
Blood Brain Barrier + 0.8356
Caco-2 permeable + 0.5851
P-glycoprotein substrate Substrate 0.7338
P-glycoprotein inhibitor I Non-inhibitor 0.5276
P-glycoprotein inhibitor II Non-inhibitor 0.9432
Renal organic cation transporter Non-inhibitor 0.8024
CYP450 2C9 substrate Non-substrate 0.7859
CYP450 2D6 substrate Non-substrate 0.846
CYP450 3A4 substrate Substrate 0.6846
CYP450 1A2 substrate Non-inhibitor 0.5204
CYP450 2C9 substrate Non-inhibitor 0.6766
CYP450 2D6 substrate Non-inhibitor 0.9217
CYP450 2C19 substrate Non-inhibitor 0.6442
CYP450 3A4 substrate Non-inhibitor 0.7319
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.7769
Ames test Non AMES toxic 0.506
Carcinogenicity Non-carcinogens 0.9434
Biodegradation Not ready biodegradable 0.9918
Rat acute toxicity 1.3725 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9531
hERG inhibition (predictor II) Non-inhibitor 0.7363
Pharmacoeconomics
Manufacturers
  • Bioenvision inc
PackagersNot Available
Dosage formsNot Available
PricesNot Available
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point264 dec °CPhysProp
logP3Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0593ALOGPS
logP2.41ALOGPS
logP2.3ChemAxon
logS-3.8ALOGPS
pKa (Strongest Acidic)5.23ChemAxon
pKa (Strongest Basic)-0.88ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area76.78 Å2ChemAxon
Rotatable Bond Count0ChemAxon
Refractivity90.17 m3·mol-1ChemAxon
Polarizability36.96 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Walter Elger, Sybille Beier, Beate Kosub, Marianne Faehnrich, Krzysztof Chwalisz, Syed Hamiduddin Hasan, Gordon Oliver Potts, “Combined use of an antigestagen and a progesterone synthesis inhibitor of the trilostane and epostane type.” U.S. Patent US5795881, issued June, 1987.

US5795881
General Reference
  1. Komanicky P, Spark RF, Melby JC: Treatment of Cushing’s syndrome with trilostane (WIN 24,540), an inhibitor of adrenal steroid biosynthesis. J Clin Endocrinol Metab. 1978 Nov;47(5):1042-51. Pubmed
External Links
ResourceLink
KEGG DrugD01180
PubChem Compound656583
PubChem Substance46507062
ChemSpider570949
ChEBI32260
ChEMBLCHEMBL1200907
Therapeutic Targets DatabaseDAP000148
PharmGKBPA164748507
WikipediaTrilostane
ATC CodesH02CA01
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSNot Available
Interactions
Drug InteractionsNot Available
Food InteractionsNot Available

Targets

1. 3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 1

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 1 P14060 Details

References:

  1. Naville D, Keeney DS, Jenkin G, Murry BA, Head JR, Mason JI: Regulation of expression of male-specific rat liver microsomal 3 beta-hydroxysteroid dehydrogenase. Mol Endocrinol. 1991 Aug;5(8):1090-100. Pubmed
  2. Takahashi M, Luu-The V, Labrie F: Inhibitory effect of synthetic progestins, 4-MA and cyanoketone on human placental 3 beta-hydroxysteroid dehydrogenase/5——4-ene-isomerase activity. J Steroid Biochem Mol Biol. 1990 Oct;37(2):231-6. Pubmed
  3. Suzuki S, Endo Y, Tanaka S, Iizuka R: Indirect immunofluorescence studies on the steroid-producing activity of hamster ova. Am J Obstet Gynecol. 1984 Jan 1;148(1):76-85. Pubmed
  4. Duffy DM, Hess DL, Stouffer RL: Acute administration of a 3 beta-hydroxysteroid dehydrogenase inhibitor to rhesus monkeys at the midluteal phase of the menstrual cycle: evidence for possible autocrine regulation of the primate corpus luteum by progesterone. J Clin Endocrinol Metab. 1994 Dec;79(6):1587-94. Pubmed
  5. Mensah-Nyagan AG, Feuilloley M, Dupont E, Do-Rego JL, Leboulenger F, Pelletier G, Vaudry H: Immunocytochemical localization and biological activity of 3 beta-hydroxysteroid dehydrogenase in the central nervous system of the frog. J Neurosci. 1994 Dec;14(12):7306-18. Pubmed
  6. Cooke GM: Differential effects of trilostane and cyanoketone on the 3 beta-hydroxysteroid dehydrogenase-isomerase reactions in androgen and 16-androstene biosynthetic pathways in the pig testis. J Steroid Biochem Mol Biol. 1996 Apr;58(1):95-101. Pubmed
  7. Igaz P, Tombol Z, Szabo PM, Liko I, Racz K: Steroid biosynthesis inhibitors in the therapy of hypercortisolism: theory and practice. Curr Med Chem. 2008;15(26):2734-47. Pubmed

2. 3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 2

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 2 P26439 Details

References:

  1. Naville D, Keeney DS, Jenkin G, Murry BA, Head JR, Mason JI: Regulation of expression of male-specific rat liver microsomal 3 beta-hydroxysteroid dehydrogenase. Mol Endocrinol. 1991 Aug;5(8):1090-100. Pubmed
  2. Cooke GM: Differential effects of trilostane and cyanoketone on the 3 beta-hydroxysteroid dehydrogenase-isomerase reactions in androgen and 16-androstene biosynthetic pathways in the pig testis. J Steroid Biochem Mol Biol. 1996 Apr;58(1):95-101. Pubmed
  3. Takahashi M, Luu-The V, Labrie F: Inhibitory effect of synthetic progestins, 4-MA and cyanoketone on human placental 3 beta-hydroxysteroid dehydrogenase/5——4-ene-isomerase activity. J Steroid Biochem Mol Biol. 1990 Oct;37(2):231-6. Pubmed
  4. Suzuki S, Endo Y, Tanaka S, Iizuka R: Indirect immunofluorescence studies on the steroid-producing activity of hamster ova. Am J Obstet Gynecol. 1984 Jan 1;148(1):76-85. Pubmed
  5. Duffy DM, Hess DL, Stouffer RL: Acute administration of a 3 beta-hydroxysteroid dehydrogenase inhibitor to rhesus monkeys at the midluteal phase of the menstrual cycle: evidence for possible autocrine regulation of the primate corpus luteum by progesterone. J Clin Endocrinol Metab. 1994 Dec;79(6):1587-94. Pubmed
  6. Mensah-Nyagan AG, Feuilloley M, Dupont E, Do-Rego JL, Leboulenger F, Pelletier G, Vaudry H: Immunocytochemical localization and biological activity of 3 beta-hydroxysteroid dehydrogenase in the central nervous system of the frog. J Neurosci. 1994 Dec;14(12):7306-18. Pubmed
  7. Igaz P, Tombol Z, Szabo PM, Liko I, Racz K: Steroid biosynthesis inhibitors in the therapy of hypercortisolism: theory and practice. Curr Med Chem. 2008;15(26):2734-47. Pubmed

3. Estrogen receptor

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: allosteric modulator

Components

Name UniProt ID Details
Estrogen receptor P03372 Details

References:

  1. Puddefoot JR, Barker S, Vinson GP: Trilostane in advanced breast cancer. Expert Opin Pharmacother. 2006 Dec;7(17):2413-9. Pubmed
  2. Puddefoot JR, Barker S, Glover HR, Malouitre SD, Vinson GP: Non-competitive steroid inhibition of oestrogen receptor functions. Int J Cancer. 2002 Sep 1;101(1):17-22. Pubmed
  3. Barker S, Malouitre SD, Glover HR, Puddefoot JR, Vinson GP: Comparison of effects of 4-hydroxy tamoxifen and trilostane on oestrogen-regulated gene expression in MCF-7 cells: up-regulation of oestrogen receptor beta. J Steroid Biochem Mol Biol. 2006 Aug;100(4-5):141-51. Epub 2006 Jun 27. Pubmed

4. Estrogen receptor beta

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: allosteric modulator

Components

Name UniProt ID Details
Estrogen receptor beta Q92731 Details

References:

  1. Puddefoot JR, Barker S, Vinson GP: Trilostane in advanced breast cancer. Expert Opin Pharmacother. 2006 Dec;7(17):2413-9. Pubmed
  2. Puddefoot JR, Barker S, Glover HR, Malouitre SD, Vinson GP: Non-competitive steroid inhibition of oestrogen receptor functions. Int J Cancer. 2002 Sep 1;101(1):17-22. Pubmed
  3. Barker S, Malouitre SD, Glover HR, Puddefoot JR, Vinson GP: Comparison of effects of 4-hydroxy tamoxifen and trilostane on oestrogen-regulated gene expression in MCF-7 cells: up-regulation of oestrogen receptor beta. J Steroid Biochem Mol Biol. 2006 Aug;100(4-5):141-51. Epub 2006 Jun 27. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:13