| Candidate ID: | R1211 |
| Source ID: | DB09070 |
| Source Type: | approved; investigational |
| Compound Type: |
small molecule
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| Compound Name: |
Tibolone
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| Synonyms: |
17-hydroxy-7alpha-methyl-19-nor-17alpha-pregn-5(10)-en-20-yn-3-one; Tibolone
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| Molecular Formula: |
C21H28O2
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| SMILES: |
[H][C@@]12CC[C@@](O)(C#C)[C@@]1(C)CC[C@]1([H])C3=C(CC(=O)CC3)C[C@@]([H])(C)[C@@]21[H]
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| Structure: |
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| DrugBank Description: |
Tibolone is a synthetic steroid hormone drug, which is mainly non-selective in its binding profile, acting as an agonist primarily at estrogen receptors (ER), with a preference for ER alpha .
Tibolone (Livial, Org OD 14), produced by Organon (West Orange, NJ), is a synthetic steroid that possesses estrogenic, androgenic and progestogenic properties. It has been used in Europe for almost 2 decades, primarily for the prevention of postmenopausal osteoporosis and the treatment of post-menopausal symptoms . Tibolone is approved in 90 countries to manage menopausal symptoms and in 45 countries to prevent the development of osteoporosis .
In June 2006, Organon Pharmaceuticals announced the receipt of a Not Approvable Letter from the U.S. Food and Drug Administration (FDA), advising the company that the New Drug Application (NDA) for tibolone had not been approved .
Interestingly, the use of tibolone in the treatment cardiovascular disease has been studied with inconclusive results . Tibolone has been to have anti-resorptive effects on bone .
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| CAS Number: |
5630-53-5
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| Molecular Weight: |
312.453
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| DrugBank Indication: |
For the relief of post-menopausal symptoms and for the prevention of osteoporosis .
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| DrugBank Pharmacology: |
Tibolone prevents bone loss and treating post-menopausal symptoms without stimulating the endometrial tissues, which may lead to malignancy. Typical, drugs that treat post-menopausal symptoms such as estrogen, have a proliferative effect on the endometrium, increasing the risk of endometrial carcinoma . The effects on the bone, brain and vaginal tissues can be explained by the estrogenic activity of tibolone. It is important to note that activity is not expressed in the endometrium. Tibolone behaves differently from estrogen plus progesterone combinations on the breast. Therefore, tibolone can be characterized as a selective estrogen activity regulator .
Tibolone has been demonstrated to be an effective agent in treating symptoms associated with menopause. A 16 week trial in 1189 women examined the effect of tibolone 2.5 mg once daily on climacteric symptoms. Women treated with tibolone showed improvement from baseline in typical menopausal symptoms including hot flashes, sweating, insomnia, and anxiety .
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| DrugBank MoA: |
This drug's effects are owed to the activity of its metabolites in various tissues .
Upon ingestion, tibolone is quickly converted into three major metabolites: _3 alpha- and 3 beta-hydroxy-tibolone_, which have oestrogenic effects, and the _Delta(4)-isomer_, which has progestogenic and androgenic effects. The specific tissue-selective effects of tibolone occur due to the metabolism, regulation of enzymes and receptor activation that varies in different tissues of the body.
The bone-conserving effects occur due to estradiol receptor activation, while the progesterone and androgen receptors are not involved in this process. Breast tissue of monkeys is not found to be stimulated after tibolone administration, as occurs with estrogen plus progesterone used in combination. This is explained by the fact that tibolone and its metabolites inhibit _sulphatase and 17 beta-hydroxysteroid dehydrogenase_ (HSD) type I and _stimulate sulphotransferase and 17 beta-HSD type II_. The combined effects of this process prevent the conversion to active estrogens.
In the uterus, the progestogenic activity of the _Delta(4)-metabolite_ and the effect on estrogen-inactivating enzymes prevent estrogenic stimulation. The mammary gland is not stimulated in currently used animal models. Tibolone has been shown to regulate estrogenic activity in several tissue types by influencing the availability of estrogenic compounds for the estradiol receptor in a selective manner .
Additionally, tibolone modulates cellular homeostasis in the breast by preventing breast tissue proliferation and stimulating cell apoptosis. Tibolone does not stimulate the endometrium because of the action of its highly stable progestogenic metabolite (Delta(4)-isomer) in combination with an effect on the sulfatase (inhibition)-sulfotransferase (stimulation) system. The estrogenic metabolites of tibolone have direct, favorable effects on the cardiovascular system and, in animal models, this drug has shown no adverse consequences.
The tissue-selective effects of tibolone are the result of metabolism, enzyme regulation and receptor activation that vary in different tissues. The bone-preserving effects of tibolone are the result of estradiol receptor activation, while other steroid receptors, mainly the progesterone and androgen receptors, are not involved in this process.
In a study of monkeys, breast tissue was not stimulated, which occurs with estrogen and progesterone, because tibolone and its metabolites inhibit _sulfatase and 17 beta-hydroxysteroid _dehydrogenase (HSD) type I and stimulate _sulfotransferase and 17 beta-HSD type II_. The simultaneous effects of this process halt conversion to active estrogens. Additionally, tibolone affects cellular homeostasis in the breast by preventing proliferation and stimulating apoptosis. Tibolone does not stimulate the endometrium due to the action of the highly stable progestogenic metabolite (Delta(4)-isomer) in combination with an effect on the sulphatase (inhibition)-sulphotransferase (stimulation) pathway .
The levels of tibolone metabolites and the alteration of hormonal activities vary according to the tissue type. In endometrial tissue the _Δ4-isomer_ functions as a progestagen, however, in the brain and liver, it shows androgenic effects. In breast tissue, the primary actions of tibolone are strong inhibition of sulfatase activity and weak inhibition of 17β-hydroxysteroid dehydrogenase activity, which leads to blocking the conversion estrone sulfate to E2 .
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| Targets: |
Estrogen receptor alpha antagonist&agonist
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| Inclusion Criteria: |
Therapeutic strategy associated
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