Identification

Name
Testolactone
Accession Number
DB00894  (APRD00640)
Type
Small Molecule
Groups
Approved, Investigational
Description

An antineoplastic agent that is a derivative of progesterone and used to treat advanced breast cancer.

Structure
Thumb
Synonyms
  • (4aS,4bR,10aR,10bS,12aS)-10a,12a-dimethyl-3,4,4a,5,6,10a,10b,11,12,12a-decahydro-2H-naphtho[2,1-f]chromene-2,8(4bH)-dione
  • 1-dehydrotestololactone
  • 1,2-didehydrotestololactone
  • 13-hydroxy-3-oxo-13,17-secoandrosta-1,4-dien-17-oic acid δ-lactone
  • D-homo-17a-oxaandrosta-1,4-diene-3,17-dione
  • delta(1)-testololactone
  • Testolactona
  • Testolactonum
  • Testolattone
  • Δ1-testololactone
External IDs
NSC-23759 / SQ 9538 / SQ-9538
International/Other Brands
Fludestrin (Bristol-Myers Squibb) / Teslac (Bristol-Myers Squibb)
Categories
UNII
6J9BLA949Q
CAS number
968-93-4
Weight
Average: 300.3921
Monoisotopic: 300.172544634
Chemical Formula
C19H24O3
InChI Key
BPEWUONYVDABNZ-DZBHQSCQSA-N
InChI
InChI=1S/C19H24O3/c1-18-9-7-13(20)11-12(18)3-4-14-15(18)8-10-19(2)16(14)5-6-17(21)22-19/h7,9,11,14-16H,3-6,8,10H2,1-2H3/t14-,15+,16+,18+,19+/m1/s1
IUPAC Name
(1R,2S,7S,10S,11R)-7,11-dimethyl-6-oxatetracyclo[8.8.0.0²,⁷.0¹¹,¹⁶]octadeca-12,15-diene-5,14-dione
SMILES
[H][[email protected]@]12CCC3=CC(=O)C=C[[email protected]]3(C)[[email protected]@]1([H])CC[[email protected]]1(C)OC(=O)CC[[email protected]@]21[H]

Pharmacology

Indication

For palliative treatment of advanced breast cancer in postmenopausal women.

Structured Indications
Not Available
Pharmacodynamics

Testolactone is a synthetic anti-neoplastic agent that is structurally distinct from the androgen steroid nucleus in possessing a six-membered lactone ring in place of the usual five-membered carbocyclic D-ring. Despite some similarity to testosterone, testolactone has no in vivo androgenic effect. No other hormonal effects have been reported in clinical studies in patients receiving testolactone.

Mechanism of action

Although the precise mechanism by which testolactone produces its clinical antineoplastic effects has not been established, its principal action is reported to be inhibition of steroid aromatase activity and consequent reduction in estrone synthesis from adrenal androstenedione, the major source of estrogen in postmenopausal women. Based on in vitro studies, the aromatase inhibition may be noncompetitive and irreversible. This phenomenon may account for the persistence of testolactone's effect on estrogen synthesis after drug withdrawal.

TargetActionsOrganism
ACytochrome P450 19A1
inhibitor
Human
Absorption

Testolactone is well absorbed from the gastrointestinal tract.

Volume of distribution
Not Available
Protein binding

~85%

Metabolism

Hepatic. Metabolized to several derivatives in the liver, all of which preserve the lactone D-ring.

Route of elimination

No clinical effects in humans of testolactone on adrenal function have been reported; however, one study noted an increase in urinary excretion of 17-ketosteroids in most of the patients treated with 150 mg/day orally. It is metabolized to several derivatives in the liver, all of which preserve the lactone D-ring. These metabolites, as well as some unmetabolized drug, are excreted in the urine.

Half life
Not Available
Clearance
Not Available
Toxicity

Oral LD50s in mouse and dog are 1630 mg/kg and 593-926 mg/kg, respectively.

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 Testolactone.Approved
AcetyldigoxinAcetyldigoxin may decrease the cardiotoxic activities of Testolactone.Experimental
BevacizumabBevacizumab may increase the cardiotoxic activities of Testolactone.Approved, Investigational
CabazitaxelThe risk or severity of adverse effects can be increased when Cabazitaxel is combined with Testolactone.Approved
CyclophosphamideCyclophosphamide may increase the cardiotoxic activities of Testolactone.Approved, Investigational
CymarinCymarin may decrease the cardiotoxic activities of Testolactone.Experimental
DeslanosideDeslanoside may decrease the cardiotoxic activities of Testolactone.Approved
DigitoxinDigitoxin may decrease the cardiotoxic activities of Testolactone.Approved, Investigational
DigoxinDigoxin may decrease the cardiotoxic activities of Testolactone.Approved
Digoxin Immune Fab (Ovine)Digoxin Immune Fab (Ovine) may decrease the cardiotoxic activities of Testolactone.Approved
DocetaxelThe risk or severity of adverse effects can be increased when Docetaxel is combined with Testolactone.Approved, Investigational
GitoformateGitoformate may decrease the cardiotoxic activities of Testolactone.Experimental
Lanatoside CLanatoside C may decrease the cardiotoxic activities of Testolactone.Experimental
MetildigoxinMetildigoxin may decrease the cardiotoxic activities of Testolactone.Experimental
OleandrinOleandrin may decrease the cardiotoxic activities of Testolactone.Experimental, Investigational
OuabainOuabain may decrease the cardiotoxic activities of Testolactone.Approved
PaclitaxelThe risk or severity of adverse effects can be increased when Paclitaxel is combined with Testolactone.Approved, Vet Approved
PeruvosidePeruvoside may decrease the cardiotoxic activities of Testolactone.Experimental
ProscillaridinProscillaridin may decrease the cardiotoxic activities of Testolactone.Experimental
TrastuzumabTrastuzumab may increase the cardiotoxic activities of Testolactone.Approved, Investigational
Food Interactions
Not Available

References

Synthesis Reference

Ivan Gilbert, Michael White, "Fermentation method for the preparation of testolactone by fusarium species." U.S. Patent US20060292666, issued December 28, 2006.

US20060292666
General References
Not Available
External Links
Human Metabolome Database
HMDB15031
KEGG Drug
D00153
KEGG Compound
C02197
PubChem Compound
13769
PubChem Substance
46508076
ChemSpider
13172
BindingDB
50367848
ChEBI
9460
ChEMBL
CHEMBL1571
Therapeutic Targets Database
DAP000624
PharmGKB
PA164743056
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
FDA label
Download (105 KB)
MSDS
Download (58.6 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentCongenital Adrenal Hyperplasia (CAH) / Growth Disorders1
2CompletedTreatmentPolyostotic Fibrous Dysplasia / Puberty, Precocious1
2CompletedTreatmentPuberty, Precocious1

Pharmacoeconomics

Manufacturers
  • Bristol myers squibb
  • Bristol myers squibb co
Packagers
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)218.5 °CPhysProp
water solubilitySlightly soluble (27.4 mg/L)Not Available
logP3.7Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.023 mg/mLALOGPS
logP2.33ALOGPS
logP3.23ChemAxon
logS-4.1ALOGPS
pKa (Strongest Acidic)18.84ChemAxon
pKa (Strongest Basic)-5ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area43.37 Å2ChemAxon
Rotatable Bond Count0ChemAxon
Refractivity85.79 m3·mol-1ChemAxon
Polarizability33.42 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9945
Blood Brain Barrier+0.9379
Caco-2 permeable+0.7355
P-glycoprotein substrateSubstrate0.6792
P-glycoprotein inhibitor IInhibitor0.6476
P-glycoprotein inhibitor IINon-inhibitor0.6498
Renal organic cation transporterNon-inhibitor0.7565
CYP450 2C9 substrateNon-substrate0.8542
CYP450 2D6 substrateNon-substrate0.9116
CYP450 3A4 substrateSubstrate0.6459
CYP450 1A2 substrateNon-inhibitor0.7315
CYP450 2C9 inhibitorNon-inhibitor0.8996
CYP450 2D6 inhibitorNon-inhibitor0.9177
CYP450 2C19 inhibitorNon-inhibitor0.8484
CYP450 3A4 inhibitorNon-inhibitor0.7612
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9224
Ames testNon AMES toxic0.9515
CarcinogenicityNon-carcinogens0.9515
BiodegradationNot ready biodegradable0.9096
Rat acute toxicity1.7356 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8719
hERG inhibition (predictor II)Non-inhibitor0.8734
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 naphthopyrans. These are compounds containing a pyran ring fused to a naphthalene moiety. Furan is a 6 membered-ring non-aromatic ring with five carbon and one oxygen atoms. Naphthalene is a polycyclic aromatic hydrocarbon made up of two fused benzene rings.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Naphthopyrans
Sub Class
Not Available
Direct Parent
Naphthopyrans
Alternative Parents
Naphthalenes / Delta valerolactones / Pyrans / Oxanes / Cyclic ketones / Carboxylic acid esters / Oxacyclic compounds / Monocarboxylic acids and derivatives / Organic oxides / Hydrocarbon derivatives
Substituents
Naphthopyran / Naphthalene / Delta valerolactone / Delta_valerolactone / Pyran / Oxane / Cyclic ketone / Lactone / Ketone / Carboxylic acid ester
Molecular Framework
Aliphatic heteropolycyclic compounds
External Descriptors
3-oxo-Delta(1),Delta(4)-steroid, seco-androstane (CHEBI:9460) / Androstane and derivatives (C02197) / C19 steroids (androgens) and derivatives (LMST02020084)

Targets

Details
1. Cytochrome P450 19A1
Kind
Protein
Organism
Human
Pharmacological action
Yes
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. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
  2. Raman JD, Schlegel PN: Aromatase inhibitors for male infertility. J Urol. 2002 Feb;167(2 Pt 1):624-9. [PubMed:11792932]
  3. Herzog AG, Klein P, Jacobs AR: Testosterone versus testosterone and testolactone in treating reproductive and sexual dysfunction in men with epilepsy and hypogonadism. Neurology. 1998 Mar;50(3):782-4. [PubMed:9521275]
  4. Dunkel L: Use of aromatase inhibitors to increase final height. Mol Cell Endocrinol. 2006 Jul 25;254-255:207-16. [PubMed:16766117]
  5. Cepa MM, Tavares da Silva EJ, Correia-da-Silva G, Roleira FM, Teixeira NA: Structure-activity relationships of new A,D-ring modified steroids as aromatase inhibitors: design, synthesis, and biological activity evaluation. J Med Chem. 2005 Oct 6;48(20):6379-85. [PubMed:16190763]

Drug created on June 13, 2005 07:24 / Updated on November 07, 2017 01:44