Abiraterone acetate

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 (IC_50'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)

The Uses of Abiraterone acetate

Abiraterone acetate is a novel steroidal inhibitor of human Cytochrome P450 (17α-Hydroxylase-C17,20-lyase): potential agent for the treatment of prostatic cancer.

The Uses of Abiraterone acetate

A novel steroidal inhibitor of human Cytochrome P450(17a-Hydroxylase-C17,20-lyase): potential agent for the treatment of prostatic cancer.

The Uses of Abiraterone acetate

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.

What are the applications of Application

Abiraterone Acetate is a steroidal inhibitor of CYP17A1 in androgen biosynthesis

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

Mechanism of action

Abiraterone acetate is converted in vivo into abiraterone, an androgen biosynthesis inhibitor that inhibits 17α- hydroxylase/C17,20-cleaving enzyme (CYP17). This enzyme is expressed in testicular, adrenal and prostate tumour tissues and is required for androgen biosynthesis. Inhibition of CYP17 by Abiraterone blocks androgen production, and inhibition of CYP17 also leads to increased production of salicorticotropin by the adrenal glands.

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.

Side Effects

The most common adverse reactions to Abiraterone acetate include: fatigue, arthralgia, hypertension, nausea, oedema, hypokalaemia, hot flushes, diarrhoea, vomiting, upper respiratory tract infection, cough and headache. Other possible side effects include: hypertension, hypokalaemia, fluid retention, prolonged QT interval, tip-twist ventricular tachycardia.

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.

storage

Store at -20°C