154229-18-2 Usage
Description
In April 2011, the United States FDA approved abiraterone acetate
(CB7630) in combination with the steroid prednisone for the treatment
of metastatic castration-resistant prostate cancer (mCRPC) for patients
who were previously treated with a docetaxel containing regimen for
late-stage disease. Abiraterone acetate affects prostate, testicular, and adrenal androgens by irreversibly inhibiting
both the lyase and hydroxylase activity of cytochrome P450 17A
(CYP17) signaling pathways (IC50's of 2.9 and 4 nM, respectively) thereby
decreasing testosterone levels.Most common serious adverse events for abiraterone acetate versus placebo included fluid retention (30.5% vs. 22.3%), hypokalemia (17.1% vs. 8.4%), hypertension (9.7% vs. 7.9%), hepatic transaminase abnormalities (10.4% vs. 8.1%), and cardiac abnormalities (13.3% vs. 10.4%).
Chemical Properties
Off-White Solid
Originator
Institute of Cancer Research, London (United Kingdom)
Uses
Different sources of media describe the Uses of 154229-18-2 differently. You can refer to the following data:
1. Abiraterone acetate is a novel steroidal inhibitor of human Cytochrome P450 (17α-Hydroxylase-C17,20-lyase): potential agent for the treatment of prostatic cancer.
2. Abiraterone acetate was approved by the U.S. Food and Drug
Administration (FDA) in April 2011 for the treatment of castrationresistant
prostate cancer. The drug, marketed under the trade name
Zytiga, was originally discovered by researchers at the Cancer Research
UK Centre for Cancer Therapeutics in 1990, developed by Cougar
Biotechnology, and ultimately commercialized by Johnson &
Johnson after its acquisition of Cougar in 2009. Abiraterone acetate
inhibits CYP17A1—an enzyme expressed in testicular, adrenal, and
prostatic tumor tissues—which has been implied in the production of
testosterone and the proliferation of such tumor cell lines.
3. A novel steroidal inhibitor of human Cytochrome P450(17a-Hydroxylase-C17,20-lyase): potential agent for the treatment of prostatic cancer.
Definition
ChEBI: A sterol ester obtained by formal condensation of the 3-hydroxy group of abiraterone with the carboxy group of acetic acid. A prodrug that is converted in vivo to abiraterone. Used for treatment of metastatic castrate-resistant prostate cance
.
Brand name
Zytiga
Biochem/physiol Actions
Abiraterone acetate is a prodrug of abiraterone, which is a potent, selective, and orally bioavailable inhibitor of CYP17A1 (CYP450c17), an enzyme that catalyzes two key serial reactions (17α hydroxylase and 17,20 lyase) in androgen and estrogen biosynthesis resulting in the formation of DHEA and androstenedione, which may ultimately be metabolized into testosterone. CYP17 is the key enzyme for androgen biosynthesis in both the testes and adrenals, so its inhibition should stop the production of androgens in both places. Abiraterone acetate is used for the treatment of metastatic castration-resistant prostate cancer. Abiraterone acetate possesses significant antitumor activity in post-docetaxel patients with CRPC (castration-resistant prostate cancer). It is highly essential for androgen biosynthesis in the testes, adrenal glands, and prostate tissue.
Clinical Use
Hormone antagonist:
Treatment of metastatic prostate cancer
Synthesis
The most convenient synthesis for scale-up will be highlighted
from two published syntheses. Commercially available
androstenolone 1 was acylated with acetic anhydride in the
presence of boron trifluoride-diethyl etherate to give a near quantitative
yield of acetate 2. The conversion of ketone 2 to vinyl triflate
3 involved careful selection of base to prevent elimination of the acetate
group. To this extent, subjection of 2 to triflic anhydride in
dichloromethane at ambient temperature followed by slow addition
of triethylamine minimized undesired side products and delivered
triflate 3 in 60% isolated yield. Subsequent Suzuki coupling with
diethylborane 4 under standard conditions ultimately furnished
abiraterone acetate (I) in 75% yield.
Drug interactions
Potentially hazardous interactions with other drugs
Antibacterials: concentration possibly reduced by
rifabutin and rifampicin - avoid.
Antidepressants: concentration possibly reduced by
St John’s wort - avoid.
Antiepileptics: concentration possibly reduced
by carbamazepine, fosphenytoin, phenobarbital,
phenytoin and primidone - avoid.
Metabolism
Abiraterone acetate is hydrolysed to abiraterone, which
then undergoes metabolism including sulphation,
hydroxylation and oxidation mainly in the liver to form
inactive metabolites. About 88% of a dose is excreted in
the faeces, of which about 55% is unchanged abiraterone
acetate and about 22% is abiraterone; about 5% of a dose
is excreted in the urine.
Check Digit Verification of cas no
The CAS Registry Mumber 154229-18-2 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 8 respectively.
Calculate Digit Verification of CAS Registry Number 154229-18:
(8*1)+(7*5)+(6*4)+(5*2)+(4*2)+(3*9)+(2*1)+(1*8)=122
122 % 10 = 2
So 154229-18-2 is a valid CAS Registry Number.
InChI:InChI=1/C26H33NO2/c1-17(28)29-20-10-12-25(2)19(15-20)6-7-21-23-9-8-22(18-5-4-14-27-16-18)26(23,3)13-11-24(21)25/h4-6,8,14,16,20-21,23-24H,7,9-13,15H2,1-3H3/t20-,21?,23?,24?,25-,26+/m0/s1
154229-18-2Relevant articles and documents
Improved procedure for preparation of abiraterone acetate
Madhra, Mukesh Kumar,Sriram, Hari Mohan,Inamdar, Murad,Sharma, Mukesh Kumar,Prasad, Mohan,Joseph, Sony
, p. 555 - 558 (2014)
An improved procedure for the preparation of abiraterone acetate is described. The present process highlights reduced reaction time, isolation with acid-base treatment without involving column chromatography, multiple crystallization and is amenable to la
Application of trifluoromethanesulfonate in preparation of abiraterone acetate and synthesis method of trifluoromethanesulfonate
-
Paragraph 0036-0045, (2021/06/12)
The invention particularly relates to application of trifluoromethanesulfonate in preparation of abiraterone acetate and a synthesis method. The invention provides a novel method for synthesizing abiraterone acetate. According to the method, a trifluoromethanesulfonate, such as iron trifluoromethanesulfonate and scandium trifluoromethanesulfonate, is adopted as a catalyst, isopropenyl acetate is adopted as an acylation reagent, and acetylation is carried out on the 3-site hydroxyl of abiraterone to synthesize abiraterone acetate. The method is simple to operate and high in product yield, and the use of irritant acetylation reagents such as acetic anhydride and acetyl chloride and chemical amounts of basic groups such as pyridine and triethylamine is avoided.
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
supporting information, 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.
Method for preparing abiraterone acetate
-
Paragraph 0143; 0148-0149, (2020/07/14)
The invention provides a method for preparing abiraterone acetate. Specifically, the invention relates to an improved method for synthesizing abiraterone or a derivative thereof through a key 3 beta-benzoyloxy intermediate. According to the process, intermediate DHEA 3-benzoyloxy ester is a solid, the intermediate with higher purity can be obtained through a crystallization method, and the processoperability is high. Meanwhile, benzoyl is strong in electric negative force, easy to react with hydroxyl and high in acylation rate, and a six-membered ring structure is twisted in a space structureof a benzoyl functional group, so that elimination reaction is not easy to perform, and generation of process byproducts is effectively avoided.