Trilostane

Trilostane Basic information
treatment of Cushing's syndrome Uses in dogs Indications Treatment history Mechanism The treatment of advanced breast cancer
Product Name:Trilostane
Synonyms:TRILOSTANE;(2-alpha,4-alpha,5-alpha,17-beta)-4,5-epoxy-17-hydroxy-3-oxoandrostane-2-car;17-beta)-ph;(4a,5a,17b)-3,17-Dihydroxy-4,5-epoxyandrost-2-ene-2-carbonitrile;5a-Androstane-2a-carbonitrile, 4a,5-epoxy-17b-hydroxy-3-oxo-;Androst-2-ene-2-carbonitrile, 4,5-epoxy-3,17-dihydroxy-, (4a,5a,17b)-;Vetoryl;4α,5-Epoxy-3,17β-dihydroxy-5α-androst-2-ene-2-carbonitrile
CAS:13647-35-3
MF:C20H27NO3
MW:329.43
EINECS:237-133-0
Product Categories:Intermediates & Fine Chemicals;Pharmaceuticals;Steroids;Inhibitor;FULVICIN;APIs
Mol File:13647-35-3.mol
Trilostane Structure
Trilostane Chemical Properties
Melting point 264 °C
alpha D25 +137.4° (c = 1 in pyridine)
Boiling point 467.02°C (rough estimate)
density 1.1213 (rough estimate)
refractive index 1.5614 (estimate)
storage temp. 2-8°C
solubility DMSO: ≥17mg/mL
pka8.57±0.70(Predicted)
form powder
color white to tan
InChIKeyKVJXBPDAXMEYOA-CXANFOAXSA-N
SMILES[C@@]123CC[C@@]4([H])[C@]5([H])CC[C@H](O)[C@@]5(C)CC[C@]4([H])[C@@]1(C)CC(C#N)=C(O)[C@@]2([H])O3 |&1:0,3,5,9,11,15,17,25,r|
CAS DataBase Reference13647-35-3(CAS DataBase Reference)
EPA Substance Registry SystemTrilostane (13647-35-3)
Safety Information
Hazard Codes Xi
Risk Statements 36/37/38-62
Safety Statements 26-36/37
WGK Germany 3
HS Code 29372900
MSDS Information
ProviderLanguage
Trilostane English
Trilostane Usage And Synthesis
treatment of Cushing's syndromeTrilostane is an inhibitor of 3β-hydroxysteroid dehydrogenase used in the treatment of Cushing's syndrome and primary hyperaldosteronism. These are both disorders where excess amounts of corticosteroid hormones are produced in the body. Corticosteroids are essential for the body to make use of carbohydrates, fats and proteins and for a normal response to stress. They are also necessary for the regulation of salt and water balance in the body. Trilostane helps prevent the production of corticosteroids, controlling the symptoms associated with these disorders.
Trilostane can also be useful in the treatment of breast cancer that has relapsed in women who have gone through menopause.
Uses in dogsTrilostane was withdrawn from the United States market in April 1994. However, it was approved in 2008 for the treatment of Cushing's disease (hyperandrenocorticism) in dogs.
It is also the first drug approved to treat both pituitary-and adrenal-dependent Cushing's in dogs.
1. has kidney or liver disease.
2. takes certain medications used to treat heart disease.
3. pregnant.
4. taking other medicines, including those available to buy without a prescription, herbal or complementary medicines.
5. had an allergic reaction to this or any other medicine.
IndicationsTrilostane can inhibit 3β-dehydrogenase in the synthesis of corticosteroids, and decrease the synthesis of cortisol and aldosterone. It also can be used in the treatment of Cushing's syndrome (hypercortisolism) and primary aldosteronism. But the efficacy to treat Cushing's syndrome (hypercortisolism) is not as metyrapone. This product also has a significant role in lowering blood testosterone levels, which may be related with that its synthesis is inhibited.
Treatment historyTrilostane, that is 4α, 5α-epoxy-2-cyano-3,17β-diol, can reversibly inhibit 3β-hydroxy steroid dehydrogenase and △5, 4-isomerase in the adrenal cortex to block the biosynthesis of mineralocorticoid and glucocorticoid. In 1980, it was approved for the treatment of hyperaldosteronism and cortisol excess disease in the United Kingdom. In 1985, it was approved for the treatment of Cushing's syndrome in the United States, which is adrenal cortex hyperactivity disorder. In view of the older animals, especially older dogs are susceptible to Cushing's syndrome. Trilostane can relieve the disease symptoms of more than 90% of dogs, and improve their quality of life. So the drug has also been granted for the treatment of animals in the United Kingdom. Trilostane itself has no hormonal activity. Its side effects is less, and its safety and tolerability are also particularly good.
The above information is edited by the chemicalbook of Ge Qian.
MechanismBreast cancer is one of hormone-dependent tumors. And estrogen is the main driving factor of the growth of breast cancer cells. Thus, one of the modern treatment of breast cancer is the major target of estrogen through inhibiting the production of estrogen or block the action of estrogen or estrogen receptor in its site of action. It has been known that estrogen receptor is only a single receptor, but recent studies have identified that there are at least two subtypes α and β. Estrogen uniting with α-estrogen can stimulate cell growth, but it uniting with β-estrogen receptor can cut α-estrogen receptors and slow the rate of cell proliferation. Research revealed that the trilostane cannot only lower the production of estrogen, but also can modulate the binding of estrogen receptors on different subtypes. And meanwhile the dual effect of α-estrogen receptor inhibitors and β-estrogen receptor appears. Finally it can block and alter the negative effect of estrogen on cancer cells. The unique mode of action of trilostane can not only set it apart from other existing anti-estrogen drugs, but also be the pharmacological basis of that it is still highly effective on breast cancer in treatment failure with other anti-estrogen therapy or resistant breast cancer.
The treatment of advanced breast cancerBreast cancer is the most common type of tumor in women. Currently, for postmenopausal patients with hormone receptor-positive or unknown, clinical treatments unanimously recommend to be the preferred antiestrogen therapy, and the role of this therapy in delaying disease progression and improving survival time also has been affirmed and confirmed in numerous studies of breast cancer.
Trilostane (trade name Modrenal) developed by the biotechnology company has already been on the market. It can be used for the treatment of postmenopausal women that hormone-selective cancer has spread outside the breast. The pharmaceutical uses two ways to slow down the disease progression. For hormone-sensitive breast cancer, estrogen promotes the growth of cancer cells by acting to the two receptors. Estrogen receptor α is cancer accelerator, and estrogen receptor β is the brake. Modrenal strengthens estrogen adsorption to the estrogen receptor β, and weakens the adsorption to estrogen receptor α. Meanwhile it also acts on another loci AP1in cell DNA to reduce cell proliferation.
Description3β-hydroxysteroid dehydrogenase (3β-HSD) type 1 and type 2 isoforms are key enzymes for the biosynthesis of all active steroid hormones. 3β-HSD1 (type I) is expressed in placenta and peripheral tissues including breast tumors, whereas 3β-HSD2 (type 2) is expressed in the adrenal gland, ovary, and testis. Trilostane is an inhibitor of the 3β-HSDs: 3β-HSD1 and 3β-HSD2 with Ki values of 0.10 and 1.60 μM, respectively. Trilsotane has been approved for use in the treatment of Cushing’s syndrome in dogs to reduce cortisol, aldosterone, and corticosterone levels. Because human 3β-HSD (type 1) is a critical enzyme in the conversion of DHEA to estradiol in breast tumors, trilostane is also of interest for the treatment of breast cancer in postmenopausal women.
Chemical PropertiesTan Crystals
OriginatorModrenal,Sterling Winthrop,UK,1980
UsesAn inhibitor of steroid biosynthesis. Used as an adrenocortical suppressant. Used in the treatment of breast cancer.
Usesantifungal, inhibits mitosis in metaphase
UsesTrilostane has been used to evaluate its capability to regulate the sex-dependent differences in the lipopolysaccharide (LPS)-induced inflammatory responses of astrocytes.
DefinitionChEBI: Trilostane is an epoxy steroid that is 3,17beta-dihydroxy-5alpha-androst-2-ene-2-carbonitrile in which the oxygen of the epoxy group is joined to the 4alpha and 5 alpha positions. It has a role as an antineoplastic agent, an abortifacient and an EC 1.1.1.210 [3beta(or 20alpha)-hydroxysteroid dehydrogenase] inhibitor. It is a 3-hydroxy steroid, a 17beta-hydroxy steroid, an androstanoid, an epoxy steroid and a nitrile.
Manufacturing Process(A)17β-acetoxy-4α,5α-epoxyandrostano[2,3-d]isoxazole, melting point 228.6°C to 229.8°C (corrected) recrystallized from a benzene-methanol mixture, [α]D25 = +76.5°C (1% in chloroform), was prepared by treating 17β- acetoxy-4-androsteno[2,3-d] isoxazole with maleic anhydride and hydrogen peroxide in methylene dichloride solution.
(B)2α-cyano-4α,5α-epoxandrostan-17β-ol-3-one was prepared by treating 17β-acetoxy-4α,5α-epoxyandrostano[2,3-d] isoxazole with sodium methoxide, and was obtained in the form of tan crystals, melting point 257.8°C to 270.0°C (decomposition) (corrected) when recrystallized from a pyridine_x0002_dioxane mixture.
Brand nameModrastane (Bioenvision).
Therapeutic FunctionCorticosteroid antagonist
General DescriptionTrilostane inhibits the production of adrenal steroids, such as cortisol and aldosterone. It is used to treat aldosteronism.
Biochem/physiol ActionsTrilostane is an inhibitor of 3 β-hydroxysteroid dehydrogenase (3-β-HSD or delta 5-delta 4-isomerase), an essential enzyme for the biosynthesis of all classes of hormonal steroids. It has been used in the treatment of Cushing′s syndrome for stopping the production of cortisol, and is currently approved for dogs in the US, but is still a human drug in the UK and other countries. It is being investigated as a possible treatment for both breast cancer and prostate cancer to prevent the synthesis of estrogens and androgens from endogenous precursors. It has also been used to inhibit endogenous production of progesterone in research studies.
Veterinary Drugs and TreatmentsTrilostane may be useful for treating pituitary-dependent hyperadrenocorticism or adrenal dependent hyperadrenocorticism in dogs, feline pituitary-dependent hyperadrenocorticism, and equine hyperadrenocorticism (HAC). It may also be useful in treating Pomeranians with Alopecia X and Alaskan malamutes with adultonset alopecia.
Trilostane Preparation Products And Raw materials
Raw materialsSodium Methoxide-->Hydrogen peroxide-->Maleic anhydride
Dodecanenitrile N-PENTADECANONITRILE 1,2-EPOXYHEXADECANE 3,5,5-TRIMETHYL-2-CYCLOHEXEN-1-OL 7-METHYLOCTANENITRILE (R)-(+)-1,2-EPOXYTRIDECANE (R)-(+)-1,2-EPOXYTETRADECANE hexadecanenitrile 6-METHYLHEPTANENITRILE N-DODECYL CYANIDE (R)-2-VINYL-OXIRANE CYCLOHEXENE-1-CARBONITRILE N-OCTYL CYANIDE (R)-(+)-1,2-EPOXY-9-DECENE BUTADIENE MONOXIDE ORANILE N-HEPTADECANONITRILE Methylenecyclohexaneoxide

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