DrugBank: Testolactone (DB00894)

targets (1)

Identification

Name

Testolactone

Accession Number

DB00894 (APRD00640)

Type

small molecule

Groups

approved

Description

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

Structure

Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure

Synonyms

Testolactona [INN-Spanish]
Testolactonum [INN-Latin]
Testolattone [Dcit]

Brand names

Fludestrin
Teolit
Teslac
Teslak
Testolacton

Brand name mixtures

Not Available

Categories

Antineoplastic Agents, Hormonal

CAS number

968-93-4

Weight

Average: 300.3921
Monoisotopic: 300.172544634

Chemical Formula

C₁₉H₂₄O₃

InChI Key

InChIKey=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

Plain Text

IUPAC Name

(1R,2S,7S,10S,11R)-7,11-dimethyl-6-oxatetracyclo[8.8.0.0^{2,7}.0^{11,16}]octadeca-12,15-diene-5,14-dione

SMILES

[H][C@@]12CCC3=CC(=O)C=C[C@]3(C)[C@@]1([H])CC[C@]1(C)OC(=O)CC[C@@]21[H]

Plain Text

Mass Spec

Not Available

Taxonomy

Kingdom

Organic

Classes

Steroids and Steroid Derivatives

Substructures

Steroids and Steroid Derivatives
Carboxylic Acids and Derivatives
Alkanes and Alkenes
Pyrans
Acetates
Lactones
Ethers
Heterocyclic compounds
Thromboxanes
Ketones

Pharmacology

Indication

For palliative treatment of advanced breast cancer in postmenopausal women.

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.

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

Pharmacoeconomics

Manufacturers

Bristol myers squibb
Bristol myers squibb co

Packagers

Dosage forms

Form	Route	Strength
Tablet	Oral

Prices

Not Available

Patents

Not Available

Properties

State

solid

Melting point

218.5 oC

Experimental Properties

Property	Value	Source
water solubility	Slightly soluble (27.4 mg/L)	PhysProp
logP	3.7	PhysProp

Predicted Properties

Property	Value	Source
water solubility	2.30e-02 g/l	ALOGPS
logP	2.33	ALOGPS
logP	3.23	ChemAxon Molconvert
logS	-4.12	ALOGPS
pKa		ChemAxon Molconvert
hydrogen acceptor count	2	ChemAxon Molconvert
hydrogen donor count	0	ChemAxon Molconvert
polar surface area	43.37	ChemAxon Molconvert
rotatable bond count	0	ChemAxon Molconvert
refractivity	85.79	ChemAxon Molconvert
polarizability	33.42	ChemAxon Molconvert

References

Synthesis Reference

Not Available

General Reference

Not Available

External Links

Resource	Link
KEGG Drug	D00153
KEGG Compound	C02197
PubChem Compound	13769
PubChem Substance	46508076
ChemSpider	13172
ChEBI	9460
ChEMBL	9460
Therapeutic Targets Database	DAP000624
PharmGKB	PA451626
Drug Product Database	0
RxList	http://www.rxlist.com/cgi/generic2/testolactone.htm
Drugs.com	http://www.drugs.com/cdi/testolactone.html

ATC Codes

Not Available

AHFS Codes

Not Available

PDB Entries

Not Available

FDA label

show (105.4 KB)

MSDS

show (58.6 KB)

Interactions

Drug Interactions

Not Available

Food Interactions

Not Available

Targets
1. Cytochrome P450 19A1 Pharmacological action: yes Actions: inhibitor Catalyzes the formation of aromatic C18 estrogens from C19 androgens Organism class: human UniProt ID: P11511 Gene: CYP19A1 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed Raman JD, Schlegel PN: Aromatase inhibitors for male infertility. J Urol. 2002 Feb;167(2 Pt 1):624-9. Pubmed 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 Dunkel L: Use of aromatase inhibitors to increase final height. Mol Cell Endocrinol. 2006 Jul 25;254-255:207-16. Pubmed 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

Targets

1. Cytochrome P450 19A1

Pharmacological action: yes
Actions: inhibitor

Catalyzes the formation of aromatic C18 estrogens from C19 androgens

Organism class: human
UniProt ID: P11511 Link_out

Gene: CYP19A1 Link_out

Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
Raman JD, Schlegel PN: Aromatase inhibitors for male infertility. J Urol. 2002 Feb;167(2 Pt 1):624-9. Pubmed
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
Dunkel L: Use of aromatase inhibitors to increase final height. Mol Cell Endocrinol. 2006 Jul 25;254-255:207-16. Pubmed
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

Comments

Drug created on June 13, 2005 07:24 / Updated on November 10, 2010 13:43

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.