Identification

Name
Trilostane
Accession Number
DB01108  (APRD01276)
Type
Small Molecule
Groups
Approved, Investigational, Vet Approved, Withdrawn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 It was withdrawn from the United States market in April 1994.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
Synonyms
  • Trilostano
  • Trilostanum
External IDs
WIN 24,540
International/Other Brands
Desopan / Modrastane / Modrenal
Categories
UNII
L0FPV48Q5R
CAS number
13647-35-3
Weight
Average: 329.4333
Monoisotopic: 329.199093735
Chemical Formula
C20H27NO3
InChI Key
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
IUPAC Name
(1S,2R,6R,8S,11S,12S,15S,16S)-5,15-dihydroxy-2,16-dimethyl-7-oxapentacyclo[9.7.0.0²,⁸.0⁶,⁸.0¹²,¹⁶]octadec-4-ene-4-carbonitrile
SMILES

Pharmacology

Indication

Used in the treatment of Cushing's syndrome. It is normally used in short-term treatment until permanent therapy is possible.

Structured Indications
Not Available
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 This product was withdrawn from the U.S. market in April 1994.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.

TargetActionsOrganism
A3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 1
inhibitor
Human
A3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 2
inhibitor
Human
AEstrogen receptor alpha
allosteric modulator
Human
AEstrogen receptor beta
allosteric modulator
Human
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
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteractionDrug group
AcetyldigitoxinAcetyldigitoxin may decrease the cardiotoxic activities of Trilostane.Approved
AcetyldigoxinAcetyldigoxin may decrease the cardiotoxic activities of Trilostane.Experimental
BevacizumabBevacizumab may increase the cardiotoxic activities of Trilostane.Approved, Investigational
CabazitaxelThe risk or severity of adverse effects can be increased when Cabazitaxel is combined with Trilostane.Approved
CyclophosphamideCyclophosphamide may increase the cardiotoxic activities of Trilostane.Approved, Investigational
CymarinCymarin may decrease the cardiotoxic activities of Trilostane.Experimental
DeslanosideDeslanoside may decrease the cardiotoxic activities of Trilostane.Approved
DigitoxinDigitoxin may decrease the cardiotoxic activities of Trilostane.Approved, Investigational
DigoxinDigoxin may decrease the cardiotoxic activities of Trilostane.Approved
Digoxin Immune Fab (Ovine)Digoxin Immune Fab (Ovine) may decrease the cardiotoxic activities of Trilostane.Approved
DocetaxelThe risk or severity of adverse effects can be increased when Docetaxel is combined with Trilostane.Approved, Investigational
GitoformateGitoformate may decrease the cardiotoxic activities of Trilostane.Experimental
Lanatoside CLanatoside C may decrease the cardiotoxic activities of Trilostane.Experimental
MetildigoxinMetildigoxin may decrease the cardiotoxic activities of Trilostane.Experimental
OleandrinOleandrin may decrease the cardiotoxic activities of Trilostane.Experimental, Investigational
OuabainOuabain may decrease the cardiotoxic activities of Trilostane.Approved
PaclitaxelThe risk or severity of adverse effects can be increased when Paclitaxel is combined with Trilostane.Approved, Vet Approved
PeruvosidePeruvoside may decrease the cardiotoxic activities of Trilostane.Experimental
ProscillaridinProscillaridin may decrease the cardiotoxic activities of Trilostane.Experimental
TrastuzumabTrastuzumab may increase the cardiotoxic activities of Trilostane.Approved, Investigational
Food Interactions
Not 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 References
  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:233687]
External Links
Human Metabolome Database
HMDB15240
KEGG Drug
D01180
KEGG Compound
C12580
PubChem Compound
656583
PubChem Substance
46507062
ChemSpider
570949
ChEBI
32260
ChEMBL
CHEMBL1200907
Therapeutic Targets Database
DAP000148
PharmGKB
PA164748507
Wikipedia
Trilostane
ATC Codes
H02CA01 — Trilostane

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2CompletedTreatmentAdenocarcinoma, Prostate / Prostate Cancer1
2TerminatedTreatmentMedical Abortion, Complete or Unspecified, Without Complication1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)264 dec °CPhysProp
logP3Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0593 mg/mLALOGPS
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
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9935
Blood Brain Barrier+0.8356
Caco-2 permeable+0.5851
P-glycoprotein substrateSubstrate0.7338
P-glycoprotein inhibitor INon-inhibitor0.5276
P-glycoprotein inhibitor IINon-inhibitor0.9432
Renal organic cation transporterNon-inhibitor0.8024
CYP450 2C9 substrateNon-substrate0.7859
CYP450 2D6 substrateNon-substrate0.846
CYP450 3A4 substrateSubstrate0.6846
CYP450 1A2 substrateNon-inhibitor0.5204
CYP450 2C9 inhibitorNon-inhibitor0.6766
CYP450 2D6 inhibitorNon-inhibitor0.9217
CYP450 2C19 inhibitorNon-inhibitor0.6442
CYP450 3A4 inhibitorNon-inhibitor0.7319
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.7769
Ames testNon AMES toxic0.506
CarcinogenicityNon-carcinogens0.9434
BiodegradationNot ready biodegradable0.9918
Rat acute toxicity1.3725 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9531
hERG inhibition (predictor II)Non-inhibitor0.7363
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 GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
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 estrane steroids. These are steroids with a structure based on the estrane skeleton.
Kingdom
Organic compounds
Super Class
Lipids and lipid-like molecules
Class
Steroids and steroid derivatives
Sub Class
Estrane steroids
Direct Parent
Estrane steroids
Alternative Parents
Secondary alcohols / Cyclic alcohols and derivatives / Oxacyclic compounds / Nitriles / Epoxides / Enols / Dialkyl ethers / Organopnictogen compounds / Hydrocarbon derivatives
Substituents
Estrane-skeleton / Cyclic alcohol / Secondary alcohol / Dialkyl ether / Enol / Oxirane / Ether / Carbonitrile / Nitrile / Organoheterocyclic compound
Molecular Framework
Aliphatic heteropolycyclic compounds
External Descriptors
17beta-hydroxy steroid, androstanoid, 3-hydroxy steroid (CHEBI:32260)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Steroid delta-isomerase activity
Specific Function
3-beta-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 3-beta-HSD enzymatic system pl...
Gene Name
HSD3B1
Uniprot ID
P14060
Uniprot Name
3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 1
Molecular Weight
42251.25 Da
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:1944305]
  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:2268554]
  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:6362415]
  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:7989460]
  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:7996177]
  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:8809191]
  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:18991633]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Steroid delta-isomerase activity
Specific Function
3-beta-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 3-beta-HSD enzymatic system pl...
Gene Name
HSD3B2
Uniprot ID
P26439
Uniprot Name
3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 2
Molecular Weight
42051.845 Da
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:1944305]
  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:8809191]
  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:2268554]
  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:6362415]
  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:7989460]
  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:7996177]
  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:18991633]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Allosteric modulator
General Function
Zinc ion binding
Specific Function
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 tissu...
Gene Name
ESR1
Uniprot ID
P03372
Uniprot Name
Estrogen receptor
Molecular Weight
66215.45 Da
References
  1. Puddefoot JR, Barker S, Vinson GP: Trilostane in advanced breast cancer. Expert Opin Pharmacother. 2006 Dec;7(17):2413-9. [PubMed:17109615]
  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:12209583]
  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:16806905]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Allosteric modulator
General Function
Zinc ion binding
Specific Function
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 m...
Gene Name
ESR2
Uniprot ID
Q92731
Uniprot Name
Estrogen receptor beta
Molecular Weight
59215.765 Da
References
  1. Puddefoot JR, Barker S, Vinson GP: Trilostane in advanced breast cancer. Expert Opin Pharmacother. 2006 Dec;7(17):2413-9. [PubMed:17109615]
  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:12209583]
  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:16806905]

Drug created on June 13, 2005 07:24 / Updated on November 07, 2017 01:46