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
A novel steroidal inhibitor of human Cytochrome P450(17a-Hydroxylase-C17,20-lyase): potential agent for the treatment of prostatic cancer.
Uses
A steroidal inhibitor of CYP17A1 in androgen biosynthesis
Uses
Abiraterone acetate is a novel steroidal inhibitor of human Cytochrome P450 (17α-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
.
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.
Enzyme inhibitor
This steroid-based antineoplastic pro-drug (FW = 391.55 g/mol; CAS
154229-18-2), also known as Zytiga?, CB-7630, and systematically as
(3β) -17- (pyridin-3-yl) androsta-5,16-dien-3-ol, is converted in vivo to
abiraterone (FW = 349.51 g/mol; CAS 154229-19-3), an androgen
biosynthesis inhibitor that targets 17-a-hydroxylase/C17,20-lyase, or
CYP17 (Ki = 2 nM), an enzyme expressed in testicular, adrenal, and
prostatic tumor tissues and required for androgen biosynthesis .
CYP17A1 catalyzes the conversion of pregnenolone (and progesterone) to
17-α-hydroxy derivatives via its 17 α-hydroxylase activity, as well as the
subsequent formation of dehydroepiandrosterone, or DHEA, (and
androstenedione) via its C17,20 lyase activity. Zytiga is effective for the
treatment of castration-resistant prostate cancer (previously known as
hormone-resistant prostate cancer). A sensitive and selective LC-MS/MS
method is available for the quantification of abiraterone acetate and
abiraterone. The major circulating metabolites of abiraterone in humans
are abiraterone sulfate and the N-oxide of abiraterone sulfate. Each of these
metabolites occur at >100 times the respective concentration of abiraterone.
The sulfate metabolite is approximately 7x more potent than abiraterone
against rat testicular microsomal CYP17.
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.
