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Exemestane

description Introduction Mechanism of action Function and Use FDA Approval for Exemestane Synthesis Arimidex Indications Usage and dosage Adverse Reactions Contraindications Clinical assessment side effects Attentions Drug interactions Specification Chemical properties Uses Producing method

CAS No.107868-30-4
Chemical Name:Exemestane
Synonyms:AROMASIN;EXALAMIDE;Exemestan;FCE-24304;PNU155971;EXEMESTANE;ExeMestine;Exemestance;Exemestane D2;ExeMestane (USP)
CBNumber:CB5760314
Molecular Formula:C20H24O2
Formula Weight:296.4
MOL File:107868-30-4.mol
Exemestane Property
Melting point : 155.13°C
storage temp. : Store at -20°C
CAS DataBase Reference: 107868-30-4(CAS DataBase Reference)
Safety
Hazard Codes : T,N
Risk Statements : 60-61-51
Safety Statements : 53-22-36/37-57
Hazardous Substances Data: 107868-30-4(Hazardous Substances Data)

Exemestane Chemical Properties,Usage,Production

description
Exemestane is an oral steroidal aromatase inhibitor that effectively suppresses in vivo aromatase activity and circulating estrogen levels in postmenopausal women with advanced breast cancer. It acts as a false substrate for the aromatase enzyme, and is processed to an intermediate that binds irreversibly to the active site of the enzyme causing its inactivation.
What Exemestane Is Used For:
(1) Exemestane is used to treat advanced breast cancer in postmenopausal women.
(2) Risk reduction for invasive breast cancer in postmenopausal women.
Introduction
Exemestane is a kind of irreversible nonsteroidal aromatase inhibitors, whose structure is similar to its substrate the natural androstenedione. It’s an effective and optional approach to treat postmenopausal women steroid-dependent breast cancer by inhibiting the aromatase to deprive estrogen. It’s used for advanced breast cancer of naturally or artificially postmenopausal women who have been treated with tamoxifen while the illness has yet to progress.
Mechanism of action
Breast cancer cell growth may be estrogen-dependent. Aromatase (exemestane) is the principal enzyme that converts androgens to estrogens both in pre- and postmenopausal women. While the main source of estrogen (primarily estradiol) is the ovary in premenopausal women, the principal source of circulating estrogens in postmenopausal women is from conversion of adrenal and ovarian androgens (androstenedione and testosterone) to estrogens (estrone and estradiol) by the aromatase enzyme in peripheral tissues. Estrogen deprivation through aromatase inhibition is an effective and selective treatment for some postmenopausal patients with hormone-dependent breast cancer. Exemestane is an irreversible, steroidal aromatase inactivator, structurally related to the natural substrate androstenedione. It acts as a false substrate for the aromatase enzyme, and is processed to an intermediate that binds irreversibly to the active site of the enzyme causing its inactivation, an effect also known as "suicide inhibition". Exemestane significantly lowers circulating estrogen concentrations in postmenopausal women, but has no detectable effect on the adrenal biosynthesis of corticosteroids or aldosterone. This reduction in serum and tumor concentrations of estrogen delays tumor growth and disease progression. Exemestane has no effect on other enzymes involved in the steroidogenic pathway up to a concentration at least 600 times higher than that inhibiting the aromatase enzyme.
Function and Use
Exemestane, steroidal aromatase inactivator, whose structure is similar with natural substrate the androstenedione of aromatase, is the pseudosubstrate of aromatase. As postmenopausal women’s estrogen is mainly transferred under the effected by aromatase in peripheral tissues with androgen (produced in adrenal cortex), this product makes the aromatase inactive through combining the irreversible active site of aromatase, and hence to significantly reduce postmenopausal estrogen level in blood circulation. This product had no obvious effect on adrenal cortical hormone biosynthesis, even if the concentration is higher than 600 times the effect of aromatase inhibition concentration, it has also no obvious effect on other enzymes in cortical hormone production.
Oral absorption of this product is rapid, and the oral bioavailability is 42%, which is influenced by the food. In postmenopausal women, the absorption rate of the drug is higher than that of the healthy subjects, and the peak concentration of blood drug is 2 ~ 4 hours after oral administration. The peak time is 1.2 hours, and is shorter than that of healthy subjects (2.9 hours). The binding rate of total protein is 90%, which is mainly related to the α-acid glycoprotein and protein. Mainly through the liver metabolism, and the metabolite is inactive 17 - hydrogen exemestane, and elimination half-time is 24h. Primarily excreted by urine or feces, each accounting for 42% of the amount of dosis.
The above information is edited by the Chemicalbook He Liao Pu.
FDA Approval for Exemestane
On October 5, 2005, the U.S. Food and Drug Administration approved exemestane tablets (Aromasin®, a product of Pfizer Inc.) for adjuvant treatment of postmenopausal women with estrogen receptor positive early breast cancer who have received two to three years of tamoxifen and are switched to exemestane for completion of a total of five consecutive years of adjuvant hormonal therapy.

Safety and efficacy were evaluated in the Intergroup Exemestane Study (IES), a double-blind, multicenter, international clinical trial in postmenopausal women with early stage breast cancer who had received two to three years of adjuvant tamoxifen. Four thousand seven hundred and twenty four patients in the intention-to-treat population were randomly assigned to either continue tamoxifen (20-30 mg/day) or switch to exemestane (25 mg/day) to complete a total of five years of adjuvant hormonal therapy.

Approval was based on an analysis of disease-free survival (DFS), defined as the time from randomization to the development of local or distant recurrence, contralateral breast cancer (cancer in the other breast), or death from any cause. After a median duration of randomized therapy of 27 months and with a median duration of follow-up of 34.5 months, DFS was significantly improved in patients who switched to exemestane compared to those who continued tamoxifen (HR=0.69, 95 percent CI: 0.58-0.82, p<0.0001).

In the hormone receptor-positive subpopulation representing about 85 percent of the trial patients, DFS was significantly improved (HR=0.65, 95 percent CI: 0.53-0.79, p=0.00001) in the exemestane arm compared to the tamoxifen arm. Overall survival was not significantly different in the two arms.
Synthesis
Take androst-4-ene-3 and 17-dione (2) as raw material, firstly condense triethyl orthoformate, n-methylaniline and 40% formaldehyde solution to get 6-methylene androst-4-ene-3 and 17-dione (3), and then make dioxidation of 2,3-dichloro-5,6-DDQ to get 1. In the oxidative dehydrogenation reaction, the addition of a certain amount of weak acid can shorten the reaction time from 15h to 8h, and the yield can be increased from 47% to 62%. This method has mild reaction conditions, simple separation with total yield of 45%. The synthetic route is as follows:
Introduction
Arimidex
ARIMIDEX is a potent and selective aromatase inhibitor undergoing evaluation as a treatment for postmenopausal women with advanced breast cancer. Studies examining the pharmacology of ARIMIDEX were conducted in both animals and humans. In animals, ARIMIDEX elicits maximal aromatase suppressive activity at a dose of approx. 0.1 mg/kg, does not alter adrenal steroid hormone biosynthesis, and at a dose of 1 mg/kg, has no other pharmacologic effects other than aromatase inhibition.
Arimidex (anastrozole) lowers estrogen levels in postmenopausal women, which may slow the growth of certain types of breast tumors that need estrogen to grow in the body.
Arimidex is used to treat breast cancer in postmenopausal women. It is often given to women whose cancer has progressed even after taking tamoxifen (Nolvadex, Soltamox).
Indications
Suitable for estrogen and progesterone receptor positive postmenopausal women with advanced breast cancer.
Usage and dosage
25mg for 1 time per day, oral admiration after meals. For patients with mild hepatic and renal insufficiency, it is not required to adjust the dosage of the drug.
Adverse Reactions
The main adverse reactions of this product are nausea, dry mouth, constipation, diarrhea, dizziness, insomnia, skin rash, fatigue, fever, edema, increased pain, vomiting, abdominal pain, increased appetite, weight gain, etc. Furthermore it’s reported to cause high blood pressure, depression, anxiety, dyspnea, cough, etc. Also there is decrease of lymphocyte count and liver function (such as alanine aminotransferase) abnormality.
Contraindications
1. Forbidden for patients allergic to this drug.
2. Forbidden for pregnant, lactation women, and kids.
Clinical assessment
Exemestane is an oral potent irreversible steroidal aromatase inhibitor. Patients on tamoxifen resistant, exemestane 25mg, qd, can get 15% to 28% of objective efficiency and 69 to 76 weeks of continuous time. Exemestane is better than megestrol acetate, which can prolong the time of disease progression. For the deterioration of patient after megestrol acetate therapy, exemestane still can reach 11% ~ 13% objective efficiency. Exemestane 25 mg/d, for non-steroidal aromatase inhibitor treatment failure patients, the objective response rate is 6.6%; there is no cross resistance between those two drugs.
side effects
Common side effects
More than 10 in every 100 people have one or more of these effects.
  1. Hot flushes and sweats – this happens in more than 1 in 5 women (22%)
  2. Painful joints or muscles – this happens in just under 1 in 5 women (18%)
  3. Tiredness (fatigue) – this happens in about 1 in 6 women (16%)
  4. Feeling or being sick – this is usually mild and can be easily controlled by anti sickness tablets. It affects more than 1 in 10 women (12%)
  5. Difficulty sleeping (insomnia) – more than 1 in 10 women have this
  6. Hair thinning affects more than 1 in 10 women
  7. Headaches
Occasional side effects
Between 1 and 10 in every 100 people have one or more of these.
  1. Loss of appetite
  2. Lowered interest in sex
  3. Stomach ache
  4. Indigestion
  5. Skin rashes – these are usually mild. Let your doctor or nurse know if you have a rash. This happens in about 1 in 10 women taking exemestane (10%)
  6. Feeling dizzy – about 1 in 10 women (10%) have some dizziness. Don't drive or operate machinery if you have this
  7. Feeling very sad, including depression
  8. Loss of bone strength – this is caused by a lack of oestrogen over a long period of time and bones may break more easily. You should have a DEXA scan to check your bone density before you start treatment
  9. Diarrhoea or constipation – if this happens it is usually mild. You should drink plenty of fluids.
  10. Vaginal bleeding occurs in less than 1 in 20 women (5%) – this mainly happens during the first few weeks of treatment when women have changed from one type of hormone therapy to another. Tell your doctor or nurse if the bleeding continues
  11. Swelling in the hands and feet caused by a build up of fluid
  12. Carpal tunnel syndrome – let your doctor or nurse know if you have any pain, tingling or weakness in your hands
Rare side effects
Fewer than 1 in 100 people have these effects.
  1. Drowsiness
  2. Muscle weakness
  3. Inflammation of the liver – let your doctor know straight away if you feel generally unwell, or have yellowing of the skin and eyes, itching, abdominal pain on the right hand side, and loss of appetite.
Attentions
1.Premenopausal women generally do not use exemestane tablets.
2.Patients in severe liver and renal function insufficiency need to use it with caution. Excessive use of exemestane can lead to increased non-fatal adverse reaction.
3.Pregnancy safety grade of this drug in FDA is D grade.
4.No special attention for the elderly to use this drug.
Drug interactions
1.This product can’t be combined with estrogen drugs, so as to avoid the effect of this product.
2.Exemestane mainly metabolized by CYP3A4, but when it’s in combination with potent CYP3A4 inhibitor (ketoconazole), pharmacokinetics of the product doesn’t change, therefore it seems that CYP isoenzyme inhibitors doesn’t have significant effect on pharmacokinetics of this product, but it does not rule out the possibility that the known CYP3A4 inducers decreases exemestane concentration in plasma.
Specification
Tablet: 25mg. Capsule: 25mg.
Chemical properties
White solid, melting point 190 ~ 192℃.
Uses
1.The second generation aromatase inhibitors, used for the treatment of metastatic breast cancer and used as adjuvant therapy for early breast cancer.
2.Pharmaceutical raw materials, is a kind of irreversible steroid body aromatase extinguishing agent, can inhibit the synthesis of estrogen, and reduce circulating estrogen levels, applicable to the progression of disease after treatment with tamoxifen in postmenopausal patients with advanced breast cancer.
Producing method
Androst-4-ene-3, 17-dione (2) and triethyl orthoformate dissolved in tetrahydrofuran and anhydrous ethanol, reacting under the presence of p-toluenesulfonic acid, and then add into N-methyl aniline and formaldehyde solution to continue the reaction. The obtained Mannich reaction product dissolved in anhydrous benzoic acid and anhydrous two alkyl, under the action of DDQ, to get exemestane, and the total yield is 45%.
Chemical Properties
white to light yellow crystal powder
Usage
An antineoplastic (hormonal)
Usage
antiinfective
Usage
Labeled Exemestane, intended for use as an internal standard for the quantification of Exemestane by GC- or LC-mass spectrometry.
Exemestane Preparation Products And Raw materials
Raw materials
p-Toluenesulfonic acid Etanol Formaldehyde Tetrahydrofuran Benzoic acid
Preparation Products
Exemestane Suppliers      Global( 179)Suppliers     
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Hubei XinyuanShun Chemical Co., Ltd. 13971561712 / 13995564702 / 027-50664929027-50664927hbeixys2001@163.comCHINA 3138 55
Wuhan DKY Technology Co.,Ltd. 027-81302011 15347069687027-81302088sales@whdky.com;2851686510@qq.comCHINA 2018 58
INTATRADE GmbH +49 3493/605464+49 3493/605470sales@intatrade.deGERMANY 3590 66
3B Pharmachem (Wuhan) International Co.,Ltd. 86-21-50328103 * 801、802、803、804 Mobile:1893055203786-21-503281093bsc@sina.comCHINA 15963 69
Arden pharmaceutical &chemical Co., Ltd +86-(0)533-3595900 13793319233+86-(0)533-3595900info@chems.com.cnCHINA 672 61
Chembest Research Laboratories Limited +86(0)21-20908456+86(0)21-58180499sales@biochembest.com; market@biochembest.comCHINA 5977 61
Capot Chemical Co., Ltd +86 (0) 571 85 58 67 180086-571-85864795sales@capotchem.comCHINA 18282 66
Pure Chemistry Scientific Inc. 001-857-928-2050 or 1-888-588-9418001-617-206-9595sales@chemreagents.comUSA 9948 62
Accela ChemBio Co.,Ltd. 021-50795510-107/109 400-066-5055021-50795055sales@accelachem.comCHINA 10202 64
Chemfun Medical Technology(Shanghai) Co., Ltd. 021-67220633 & 021-37212706+86-21-67220638chemfun@chemfun.netCHINA 21914 59
 
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