Abiraterone Chemical Properties

Melting point:

227-228 °C(Solv: toluene (108-88-3))

Boiling point:

500.2±50.0 °C(Predicted)

Density 

1.14±0.1 g/cm3(Predicted)

storage temp. 

2-8°C

solubility 

Chloroform (Slightly), Methanol (Slightly)

form 

Solid

pka

14.71±0.70(Predicted)

color 

White to Pale Yellow

CAS DataBase Reference

154229-19-3

Abiraterone Usage And Synthesis

description

Abiraterone is a new type of hormone therapy. It is also called abiraterone acetate, CB7630 or Zytiga. It is used to treat prostate cancer that has spread to other parts of the body. It may help some men to live longer. It can also help control symptoms. Clinical trials are also using abiraterone for earlier stages of prostate cancer and advanced breast cancer. Abiraterone is associated with a not uncommon rate of serum enzyme elevation during therapy, but has not been clearly linked to cases of clinically apparent liver injury with jaundice.

On April 28, 2011, the U.S. Food and Drug Administration approved abiraterone acetate (Zytiga Tablets, Centocor Ortho Biotech, Inc.) for use in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have received prior chemotherapy containing docetaxel.

Abiraterone is a steroidal compound with antiandrogen activity. it is a Cytochrome P450 17A1 Inhibitor. The mechanism of action of abiraterone is as a Cytochrome P450 17A1 Inhibitor, and Cytochrome P450 2D6 Inhibitor, and Cytochrome P450 2C8 Inhibitor that catalyzes the 17alpha-hydroxylation of steroid intermediates involved in testosterone synthesis. Administration of this agent may suppress testosterone production by both the testes and the adrenals to castrate-range levels.

figure 1: Zytiga (abiraterone acetate)

Therapeutic agent for prostate cancer

Currently, for patients of advanced prostate cancer, androgen deprivation therapy including drugs and surgery is generally the preferred method of including drugs and surgery in order to reduce the testicular androgen synthesis. However, this treatment can’t suppress other parts of the body for yielding the male hormone.
Abiraterone is a therapeutic agent for prostate cancer with the English name for Abiraterone. It has not yet been marketed in China. It is developed by researchers coming from the British Royal Marsden Hospital located in southwest (world-renowned cancer research treatment center). It is kind of drug which is able to repress any part of the body for androgen production. It can not only reduce the levels of the prostate-specific antigen (PSA) which represents the tumor activity, but also helps to shrink the tumor. It can also apply to cancer patients who have been subject to chemotherapy in the past, revealing treatment hope.
Previously, the patent of the Abiraterone was owned by British Cougar biopharmaceutical Company. But in 2009 Johnson Pharmaceutical acquire the Cougar Biological Company with $ 970 million, and thus getting the permission of the drug. The phase III clinical trial results have showed that the goods can significantly prolong patients with advanced prostate cancer including those who had used one or two docetaxel chemotherapy but still got deteriorating lives with a small drug side effects and good safety.
Abiraterone is an oral administrated cytochrome oxidase P450 (CYP450) c17 inhibitor which can decrease the androgen levels through inhibiting the key enzyme in the androgen synthesis--CYP450c17, and also has inhibitory effect on the androgens coming from testis and other body parts.
The above information is edited by the chemicalbook of Dai Xiongfeng.

How abiraterone works

Hormones are substances produced naturally in the body. They act as chemical messengers and help control the activity of cells and organs. Hormonal therapies interfere with the way hormones are made or how they work in the body.
Most prostate cancers need the hormone testosterone to grow. Almost all testosterone in men is made by the testicles. A very small amount is made by the adrenal glands, which sit above the kidneys.
Abiraterone reduces the amount of testosterone made by your body. This reduces testosterone levels and may shrink the prostate cancer or stop it growing.
References
Abiraterone acetate (Zytiga®)
Abiraterone acetate (often shortened to abiraterone) is a hormonal therapy drug used to treat advanced prostate cancer. It is also known as Zytiga®.

Mechanism of Action

Abiraterone is an orally active inhibitor of the steroidal enzyme CYP17A1 (17 alpha-hydroxylase/C17,20 lyase). It inhibits CYP17A1 in a selective and irreversible manner via covalent binding mechanism. CYP17A1 is an enzyme that catalyzes the biosynthesis of androgen and is highly expressed in testicular, adrenal, and prostatic tumor tissue. More specifically, abiraterone inhibits the conversion of 17-hydroxyprognenolone to dehydroepiandrosterone (DHEA) by the enzyme CYP17A1 to decrease serum levels of testosterone and other androgens.
References
http://www.drugbank.ca/drugs/DB05812

side effects

Like all treatments, abiraterone can cause side effects. Taking prednisolone as well as abiraterone will reduce the risk of side effects. Most men don’t have many problems with side effects. Possible side effects include:

• fluid retention, which can cause swelling in your ankles or hands
• High blood pressure during treatment happens in about 1 in 10 men (10%)
• Abiraterone can also cause the level of potassium in your blood to drop. This could make you feel tired and you may be at risk of a fast, irregular heartbeat.
• Tiredness (fatigue) and breathlessness from a drop in red blood cells (anaemia)
• Swelling of the legs or feet due to fluid build up (known as peripheral oedema) affects about 3 in 10 men (30%)
• Diarrhoea – drink plenty of fluids.
• Bladder infections affect just over 1 in 10 men (10%)

Occasional side effects
Between 1 and 10 in every 100 people have one or more of these.

• A mild effect on the liver that is unlikely to cause symptoms and will almost certainly go back to normal when you finish treatment.
• Heart problems, including a faster heart beat, a change to the heart rhythm and chest pain.
• Bone thinning (osteoporosis) can make bones more likely to break.
• High fat (cholesterol) levels in your blood – your doctor will check for this.
• An increased risk of getting an infection from a drop in white blood cells – it is harder to fight infections and you can become very ill. You may have headaches, aching muscles, a cough, a sore throat, or you may feel cold and shivery. If you have a severe infection this can be life threatening. Contact your treatment centre if you have any of these side effects or if your temperature goes above 38°C.
• A skin rash – you may develop a rash, which can be itchy.

Speak to your doctor if you notice anything unusual.

Biological Activity

Description
Abiraterone is a potent CYP17 inhibitor with IC50 of 2 nM in a cell-free assay.
Features
Approved for the treatment of docetaxel-treated castration-resistant prostate cancer.
Targets  
CYP17 [1](Cell-free assay) 2 nM
In vitro  
Abiraterone binds and inhibits wild-type and mutant androgen receptor (AR). Abiraterone inhibits in vitro proliferation and androgen receptor-regulated gene expression of androgen receptor-positive prostate cancer cells, which could be explained by androgen receptor antagonism in addition to inhibition of steroidogenesis. In fact, activation of mutant androgen receptor by eplerenone is inhibited by greater concentrations of Abiraterone. Abiraterone displaces ligand from both WT-AR and T877A with EC50 of 13.4 μM and 7.9 μM, respectively. [2]Abiraterone inhibits lyase activity with an IC50 of 5.8 nM in rat testis microsomes. Abiraterone acetate significantly inhibits T secretion (−48%) and in turn increased LH concentration (192%).[3]
In vivo
Abiraterone inhibits CYP17 with an IC50 of 72 nM, in human testicular microsomes. [4] Abiraterone fails to significantly reduce the size of any of the organs. [5] Abiraterone reduces the testosterone levels strongly, almost reaching the level of the orchiectomy control. The testosterone levels are reduced by Abiraterone for more than 95% compared to the control group. [6]

References
    [1] Attard G, et al. J Clin Oncol. 2008, 26(28), 4563-4571.
    [2] Richards J, et al. Cancer Res. 2012, 72(9), 2176-2182.
    [3] Duc I, et al. J Steroid Biochem Mol Biol. 2003, 84(5), 537-542.
    [4] Hu Q, et al. J Med Chem. 2010, 53(15), 5749-5758.
    [5] Bruno RD, et al. Steroids. 2011, 76(12), 1268-1279.
    [6] Haidar S, et al. J Steroid Biochem Mol Biol. 2003, 84(5),555

Chemical Properties

White Solid

Originator

Abiraterone,Cougar

Uses

Prasteronyl Abiraterone is a dimer impurity of Abiraterone (A108490), a steroidal cytochrome P 450 17α-hydroxylase-17,20-lyase inhibitor (CYP17), is currently undergoing phase II clinical trials as a potential drug for the treatment of androgen-dependent prostate cancer.

Uses

Abiraterone, a steroidal cytochrome P 450 17α-hydroxylase-17,20-lyase inhibitor (CYP17), is currently undergoing phase II clinical trials as a potential drug for the treatment of androgen-dependent pr ostate cancer.

Definition

ChEBI: A 3beta-sterol that is androsta-5,16-dien-3beta-ol substituted at position 17 by a 3-pyridyl group. Administered as the O-acetate, it is used for treatment of metastatic castrate-resistant prostate cance .

Manufacturing Process

Diethyl(3-pyridyl)borane (3.38 g, 23 mmol) from Aldrich Chemical Co. Ltd. was added to a stirred solution of 3β-acetoxyandrosta-5,16-dien-17-yl trifluoromethanesulphonate (6.94 g, 15 mmol) in THF (75 ml) containing bis(triphenylphosphine)palladium(II) chloride (0.105 g, 0.15 mmol). An aqueous solution of sodium carbonate (2 M, 30 ml) was then added and the mixture heated, with stirring, by an oil bath at 80°C for 1 h, and allowed to cool. The mixture was partitioned between diethyl ether and water, the ether phase was dried (Na2CO3), filtered through a short plug of silica, and concentrated. Chromatography, on elution with light petroleum-diethyl ether (2:1), afforded the 3β-acetoxy-17-(3-pyridyl)androsta-5,16-diene (4.95 g, 84%) which crystallised from hexane, m.p. 144-145°C.
To a solution of 3β-acetoxy-17-(3-pyridyl)androsta-5,16-diene (4.90 g, 12.5 mmol) in methanol (50 ml) was added an aqueous solution of sodium hydroxide (10% w/v, 10 ml) and the mixture heated, with stirring, on an oil bath at 80°C for 5 min, then allowed to cool. The mixture was poured into water, neutralised with hydrochloric acid (1 M), rebasified with saturated sodium bicarbonate solution, and extracted with hot toluene. The toluene extracts were combined, dried (Na2CO3), and concentrated. Chromatography, on elution with toluene-diethyl ether (2:1) afforded the 17-(3- pyridyl)androsta-5,16-dien-3β-ol (3.45 g, 79%) which crystallised from toluene, m.p. 228-229°C.

Therapeutic Function

Antiandrogen

Biological Activity

abiraterone (17-(3-pyridyl)androsta-5,16-dien-3β-ol) is a potent small-molecule inhibitor of cyp17 complex (17 alpha-monooxygenase) which is a member of the cytochrome p450 family consisting of 17 alpha-hydroxylase and c17,20-lyase and catalyzing the 17 alpha-hydroxylation of intermediates of steroid biosynthesis involved in testerone sysnthesis. abiraterone inhibits cyp17 complex by binding to the haem iron of cyp17a1, which forms a 60o angle above the haem plane and packs against the central i helix with 3β-oh interacting with aspargine 202 in the f helix. abiraterone is currently being investigated to treat late stage prostate cancer, in which it consistently suppresses testosterone levels, leads to significant reduction in psa level, and prolong life in patients with castration-resistant prostate cancer (crpc).natasha m. devore and emily e. scott. structures of cytochrome p450 17a1 with prostate cancer drugs abiraterone and tok-001. nature 2012; 482: 116-120farshid dayyani, gary e. gallick, christopher j. logothetis, paul g. corn. novel therapies for metastatic castrate-resistant prostate cancer. jnci j natl cancer inst (2011); 103(22): 1665-1675

target

CYP17

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