154229-19-3 Usage
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 lookchem 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.Referenceshttp://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
Different sources of media describe the Biological Activity of 154229-19-3 differently. You can refer to the following data:
1. 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
2. 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
Chemical Properties
White Solid
Originator
Abiraterone,Cougar
Uses
Different sources of media describe the Uses of 154229-19-3 differently. You can refer to the following data:
1. 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.
2. 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
Check Digit Verification of cas no
The CAS Registry Mumber 154229-19-3 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,5,4,2,2 and 9 respectively; the second part has 2 digits, 1 and 9 respectively.
Calculate Digit Verification of CAS Registry Number 154229-19:
(8*1)+(7*5)+(6*4)+(5*2)+(4*2)+(3*9)+(2*1)+(1*9)=123
123 % 10 = 3
So 154229-19-3 is a valid CAS Registry Number.
InChI:InChI=1/C24H31NO/c1-23-11-9-18(26)14-17(23)5-6-19-21-8-7-20(16-4-3-13-25-15-16)24(21,2)12-10-22(19)23/h3-5,7,13,15,18-19,21-22,26H,6,8-12,14H2,1-2H3/t18-,19-,21-,22-,23-,24+/m0/s1
154229-19-3Relevant articles and documents
Synthesis and biological evaluation of analogs of didehydroepiandrosterone as potential new anticancer agents
Hansen, Trond Vidar,Liekens, Sandra,Solu, Eirik J.
, (2020)
The synthesis, cytotoxicity and inhibition of CDK8 by thirteen analogs of cortistatin A are reported. These efforts revealed that the analogs with either a 6- or 7-isoquinoline or 5-indole side chain in the 17-position are the most promising anti-proliferative agents. These compounds showed potent cytotoxic effects in CEM, HeLa and HMEC-1 cells. All three compounds exhibited IC50 values 10μM. The most interesting 10l analog exhibited an IC50 value of 0.59 μM towards the human dermal microvascular endothelial cell line (HMEC-1), significantly lower than the reference standard 2-methoxyestradiol. At a concentration at 50 nM the most potent 10h compound reduced the activity of CDK8 to 35percent.
Preparation method of abiraterone
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Paragraph 0047; 0049-0051; 0053-0055; 0057-0067, (2022/01/04)
The invention provides a preparation method of abiraterone, and belongs to the technical field of medicine synthesis. The preparation method comprises the following steps: by taking a compound 17-bromoandrostane-5, 16-diene-3beta-alcohol as an initial raw material, carrying out borylation reaction on the initial raw material and boric acid ester under the action of an accelerant to obtain an intermediate compound 2; and allowing the compound 2 and a pyridyl compound to be subjected to a coupling reaction under the action of a catalyst to obtain the abiraterone. According to the method, the yield and the purity of abiraterone are remarkably improved by adjusting the synthesis route, the ratio of the reaction raw materials and other process parameters; the preparation method disclosed by the invention is simple and easy to implement and mild in condition, the yield of the obtained product is as high as 95%, the purity of the product is as high as 99.8%, and the stipulation of the drug quality standard is met.
Slow-, tight-binding inhibition of CYP17A1 by abiraterone redefines its kinetic selectivity and dosing regimen
Cheong, Eleanor Jing Yi,Nair, Pramod C.,Neo, Rebecca Wan Yi,Tu, Ho Thanh,Lin, Fu,Chiong, Edmund,Esuvaranathan, Kesavan,Fan, Hao,Szmulewitz, Russell Z.,Peer, Cody J.,Figg, William D.,Chai, Christina Li Lin,Miners, John O.,Chan, Eric Chun Yong
, p. 438 - 451 (2020/09/04)
Substantial evidence underscores the clinical efficacy of inhibiting CYP17A1-mediated androgen biosynthesis by abiraterone for treatment of prostate oncology. Previous structural analysis and in vitro assays revealed inconsistencies surrounding the nature and potency of CYP17A1 inhibition by abiraterone. Here, we establish that abiraterone is a slow-, tight-binding inhibitor of CYP17A1, with initial weak binding preceding the subsequent slow isomerization to a high-affinity CYP17A1-abiraterone complex. The in vitro inhibition constant of the final high-affinity CYP17A1-abiraterone complex ( ( Ki? = 0.39 nM )yielded a binding free energy of -12.8 kcal/mol that was quantitatively consistent with the in silico prediction of 214.5 kcal/mol. Prolonged suppression of dehydroepiandrosterone (DHEA) concentrations observed in VCaP cells after abiraterone washout corroborated its protracted CYP17A1 engagement. Molecular dynamics simulations illuminated potential structural determinants underlying the rapid reversible binding characterizing the two-step induced-fit model. Given the extended residence time (42 hours) of abiraterone within the CYP17A1 active site, in silico simulations demonstrated sustained target engagement even whenmost abiraterone has been eliminated systemically. Subsequent pharmacokineticpharmacodynamic (PK-PD) modeling linking time-dependent CYP17A1 occupancy to in vitro steroidogenic dynamics predicted comparable suppression of downstream DHEA-sulfate at both 1000- and 500-mg doses of abiraterone acetate. This enabled mechanistic rationalization of a clinically reported PK-PD disconnect, inwhich equipotent reduction of downstreamplasma DHEAsulfate levels was achieved despite a lower systemic exposure of abiraterone. Our novel findings provide the impetus for reevaluating the current dosing paradigmof abiraterone with the aim of preserving PD efficacy while mitigating its dose-dependent adverse effects and financial burden. SIGNIFICANCE STATEMENT With the advent of novel molecularly targeted anticancer modalities, it is becoming increasingly evident that optimal dose selection must necessarily be predicated on mechanistic characterization of the relationships between target exposure, drug-target interactions, and pharmacodynamic endpoints. Nevertheless, efficacy has always been perceived as being exclusively synonymous with affinity-based measurements of drug-target binding. This work demonstrates how elucidating the slow-, tight-binding inhibition of CYP17A1 by abiraterone via in vitro and in silico analyses was pivotal in establishing the role of kinetic selectivity in mediating time-dependent CYP17A1 engagement and eventually downstream efficacy outcomes.
