Testolactone - DrugBank

ID Pharmacology Interactions References Trials Economics Properties Spectra Taxonomy

Targets (1)

Targets (1)Biointeractions (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.

Structure

MOL SDF 3D-SDF PDB SMILES InChI View 3D Structure

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

Product Ingredients

Not Available

Approved Prescription Products

Not Available

Approved Generic Prescription Products

Not Available

Approved Over the Counter Products

Not Available

Unapproved/Other Products

Not Available

International Brands

Name	Company
Fludestrin	Bristol-Myers Squibb
Teslac	Bristol-Myers Squibb

Brand mixtures

Not Available

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.

Target	Kind	Pharmacological action	Actions	Organism	UniProt ID
Cytochrome P450 19A1	Protein	yes	inhibitor	Human	P11511	details

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

Drug	Interaction	Drug group
Acetyldigitoxin	Acetyldigitoxin may decrease the cardiotoxic activities of Testolactone.	Approved
Bevacizumab	Bevacizumab may increase the cardiotoxic activities of Testolactone.	Approved, Investigational
Cabazitaxel	The risk or severity of adverse effects can be increased when Cabazitaxel is combined with Testolactone.	Approved
Cyclophosphamide	Cyclophosphamide may increase the cardiotoxic activities of Testolactone.	Approved, Investigational
Deslanoside	Deslanoside may decrease the cardiotoxic activities of Testolactone.	Approved
Digitoxin	Digitoxin may decrease the cardiotoxic activities of Testolactone.	Approved
Digoxin	Digoxin may decrease the cardiotoxic activities of Testolactone.	Approved
Docetaxel	The risk or severity of adverse effects can be increased when Docetaxel is combined with Testolactone.	Approved, Investigational
Oleandrin	Anvirzel may decrease the cardiotoxic activities of Testolactone.	Experimental
Ouabain	Ouabain may decrease the cardiotoxic activities of Testolactone.	Approved
Paclitaxel	The risk or severity of adverse effects can be increased when Paclitaxel is combined with Testolactone.	Approved, Vet Approved
Trastuzumab	Trastuzumab 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

Resource	Link
Human Metabolome Database (HMDB)	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	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

Download (105 KB)

MSDS

Download (58.6 KB)

Clinical Trials

Phase	Status	Purpose	Conditions	Count
1	Completed	Treatment	Congenital Adrenal Hyperplasia (CAH) / Growth Disorders	1
2	Completed	Treatment	Polyostotic Fibrous Dysplasia / Puberty, Precocious	1
2	Completed	Treatment	Puberty, Precocious	1

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

Property	Value	Source
melting point (°C)	218.5 °C	PhysProp
water solubility	Slightly soluble (27.4 mg/L)	Not Available
logP	3.7	Not Available

Predicted Properties

Property	Value	Source
Water Solubility	0.023 mg/mL	ALOGPS
logP	2.33	ALOGPS
logP	3.23	ChemAxon
logS	-4.1	ALOGPS
pKa (Strongest Acidic)	18.84	ChemAxon
pKa (Strongest Basic)	-5	ChemAxon
Physiological Charge	0	ChemAxon
Hydrogen Acceptor Count	2	ChemAxon
Hydrogen Donor Count	0	ChemAxon
Polar Surface Area	43.37 Å²	ChemAxon
Rotatable Bond Count	0	ChemAxon
Refractivity	85.79 m³·mol^-1	ChemAxon
Polarizability	33.42 Å³	ChemAxon
Number of Rings	4	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	Yes	ChemAxon
Veber's Rule	No	ChemAxon
MDDR-like Rule	No	ChemAxon

Predicted ADMET features

Property	Value	Probability
Human Intestinal Absorption	+	0.9945
Blood Brain Barrier	+	0.9379
Caco-2 permeable	+	0.7355
P-glycoprotein substrate	Substrate	0.6792
P-glycoprotein inhibitor I	Inhibitor	0.6476
P-glycoprotein inhibitor II	Non-inhibitor	0.6498
Renal organic cation transporter	Non-inhibitor	0.7565
CYP450 2C9 substrate	Non-substrate	0.8542
CYP450 2D6 substrate	Non-substrate	0.9116
CYP450 3A4 substrate	Substrate	0.6459
CYP450 1A2 substrate	Non-inhibitor	0.7315
CYP450 2C9 inhibitor	Non-inhibitor	0.8996
CYP450 2D6 inhibitor	Non-inhibitor	0.9177
CYP450 2C19 inhibitor	Non-inhibitor	0.8484
CYP450 3A4 inhibitor	Non-inhibitor	0.7612
CYP450 inhibitory promiscuity	Low CYP Inhibitory Promiscuity	0.9224
Ames test	Non AMES toxic	0.9515
Carcinogenicity	Non-carcinogens	0.9515
Biodegradation	Not ready biodegradable	0.9096
Rat acute toxicity	1.7356 LD50, mol/kg	Not applicable
hERG inhibition (predictor I)	Weak inhibitor	0.8719
hERG inhibition (predictor II)	Non-inhibitor	0.8734

ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum Type	Description	Splash Key
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS	Not Available
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Positive	Not Available
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Positive	Not Available
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Positive	Not Available
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Negative	Not Available
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Negative	Not Available
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Negative	Not 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

Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]
Raman JD, Schlegel PN: Aromatase inhibitors for male infertility. J Urol. 2002 Feb;167(2 Pt 1):624-9. [PubMed:11792932 ]
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 ]
Dunkel L: Use of aromatase inhibitors to increase final height. Mol Cell Endocrinol. 2006 Jul 25;254-255:207-16. [PubMed:16766117 ]
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 September 01, 2017 10:33

Structure for DB00894 (Testolactone)

Targets

References