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IdentificationPharmacologyInteractionsReferencesTrialsEconomicsPropertiesSpectraTaxonomyTestolactone
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
Structure for Testolactone (DB00894)
- 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
- Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Teslac Tablet 50 mg/1 Oral E.R. Squibb & Sons, L.L.C. 2009-06-01 2010-04-30 US 
- 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][C@@]12CCC3=CC(=O)C=C[C@]3(C)[C@@]1([H])CC[C@]1(C)OC(=O)CC[C@@]21[H]
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.
Target Actions Organism ACytochrome P450 19A1 inhibitorHuman - 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 Acetaminophen Acetaminophen may decrease the excretion rate of Testolactone which could result in a higher serum level. Acetyldigitoxin Acetyldigitoxin may decrease the cardiotoxic activities of Testolactone. Acetyldigoxin Acetyldigoxin may decrease the cardiotoxic activities of Testolactone. Acetylsalicylic acid Acetylsalicylic acid may decrease the excretion rate of Testolactone which could result in a higher serum level. Alprazolam Alprazolam may decrease the excretion rate of Testolactone which could result in a higher serum level. Amiloride Amiloride may increase the excretion rate of Testolactone which could result in a lower serum level and potentially a reduction in efficacy. Amitriptyline Testolactone may decrease the excretion rate of Amitriptyline which could result in a higher serum level. Amlodipine Amlodipine may decrease the excretion rate of Testolactone which could result in a higher serum level. Amoxicillin Testolactone may decrease the excretion rate of Amoxicillin which could result in a higher serum level. Amphetamine Amphetamine may decrease the excretion rate of Testolactone which could result in a higher serum level. - 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
- HMDB0015031
- 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
- Wikipedia
- Testolactone
- FDA label
- Download (105 KB)
- MSDS
- Download (58.6 KB)
Clinical Trials
- 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
- B&B Pharmaceuticals
- Bristol-Myers Squibb Co.
- E.R. Squibb and Sons LLC
- Dosage forms
Form Route Strength Tablet Oral 50 mg/1 - 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
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted GC-MS Spectrum - GC-MS Predicted GC-MS Not Available Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS 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
- 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 August 02, 2018 04:28