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Identification
Name Trilostane
Accession Number DB01108 (APRD01276)
Type small molecule
Groups approved, withdrawn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 It was withdrawn from the United States market in April 1994.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
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms Not Available
Salts Not Available
Brand names
Name Company
Desopan
Modrastane
Modrenal
Brand mixtures Not Available
Categories
  • Antiadrenal
  • Anticorticosteroids
CAS number 13647-35-3
Weight Average: 329.4333
Monoisotopic: 329.199093735
Chemical Formula C20H27NO3
InChI Key InChIKey=KVJXBPDAXMEYOA-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
Plain Text
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
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Steroids and Steroid Derivatives
Substructures
  • Glycerol and Derivatives
  • Hydroxy Compounds
  • Nitriles and Derivatives
  • Ethers
  • Cyanides
  • Heterocyclic compounds
  • Steroids and Steroid Derivatives
  • Alcohols and Polyols
  • Cyclohexenes and Derivatives
  • Epoxides
  • Enols
Pharmacology
Indication Used in the treatment of Cushing's syndrome. It is normally used in short-term treatment until permanent therapy is possible.
Pharmacodynamics Trilostane 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 This product was withdrawn from the U.S. market in April 1994.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 action Trilostane 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.
Absorption Not Available
Volume of distribution Not Available
Protein binding Not Available
Metabolism
Hepatic.
Route of elimination Not Available
Half life 8 hours.
Clearance Not Available
Toxicity Symptoms 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
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Bioenvision inc
Packagers Not Available
Dosage forms Not Available
Prices Not Available
Patents Not Available
Properties
State solid
Experimental Properties
Property Value Source
melting point 264 dec °C PhysProp
logP 3 Not Available
Predicted Properties
Property Value Source
water solubility 5.93e-02 g/l ALOGPS
logP 2.41 ALOGPS
logP 2.3 ChemAxon
logS -3.8 ALOGPS
pKa (strongest acidic) 5.23 ChemAxon
pKa (strongest basic) -0.88 ChemAxon
physiological charge -1 ChemAxon
hydrogen acceptor count 4 ChemAxon
hydrogen donor count 2 ChemAxon
polar surface area 76.78 ChemAxon
rotatable bond count 0 ChemAxon
refractivity 90.17 ChemAxon
polarizability 36.96 ChemAxon
References
Synthesis Reference Not Available
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
Resource Link
KEGG Drug D01180 Link_out
PubChem Compound 656583 Link_out
PubChem Substance 46507062 Link_out
ChemSpider 570949 Link_out
ChEBI 32260 Link_out
ChEMBL 32260 Link_out
Therapeutic Targets Database DAP000148 Link_out
PharmGKB PA164748507 Link_out
Wikipedia http://en.wikipedia.org/wiki/Trilostane Link_out
ATC Codes
  • H02CA01
AHFS Codes Not Available
PDB Entries Not Available
FDA label Not Available
MSDS Not Available
Interactions
Drug Interactions Not Available
Food Interactions Not Available
Targets

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

Pharmacological action: yes
Actions: inhibitor

3beta-HSD is a bifunctional enzyme, that catalyzes the oxidative conversion of delta(5)-ene-3-beta-hydroxy steroid, and the oxidative conversion of ketosteroids. The 3beta-HSD enzymatic system plays a crucial role in the biosynthesis of all classes of hormonal steroids

Organism class: human
UniProt ID: P14060 Link_out
Gene: HSD3B1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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 II

Pharmacological action: yes
Actions: inhibitor

3beta-HSD is a bifunctional enzyme, that catalyzes the oxidative conversion of delta(5)-ene-3-beta-hydroxy steroid, and the oxidative conversion of ketosteroids. The 3beta-HSD enzymatic system plays a crucial role in the biosynthesis of all classes of hormonal steroids

Organism class: human
UniProt ID: P26439 Link_out
Gene: HSD3B2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Pharmacological action: yes
Actions: allosteric modulator

Nuclear hormone receptor. The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues

Organism class: human
UniProt ID: P03372 Link_out
Gene: ESR1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Pharmacological action: yes
Actions: allosteric modulator

Nuclear hormone receptor. Binds estrogens with an affinity similar to that of ESR1, and activates expression of reporter genes containing estrogen response elements (ERE) in an estrogen-dependent manner. Isoform beta-cx lacks ligand binding ability and has no or only very low ere binding activity resulting in the loss of ligand-dependent transactivation ability. DNA- binding by ESR1 and ESR2 is rapidly lost at 37 degrees Celsius in the absence of ligand while in the presence of 17 beta-estradiol and 4-hydroxy-tamoxifen loss in DNA-binding at elevated temperature is more gradual

Organism class: human
UniProt ID: Q92731 Link_out
Gene: ESR2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
Comments
Drug created on June 13, 2005 07:24 / Updated on February 08, 2013 16:19