ChEMBL Resources

The SARfaris: GPCR, Kinase, ADME

Wednesday, 19 September 2012

New Drug Approvals 2012 - Pt. XIX - Enzalutamide (Xtandi capsulesTM)

On August 31, the FDA approved Enzalutamide for the treatment of castration-resistant prostate cancer. Prostate cancer affects predominantly men aged 50 years and older and is the sixth most frequent source of cancer-related deaths in men world-wide.

The prostate is a gland located below the bladder that surrounds the urethra and secretes simple sugars, citrate, zinc and other constituents of liquid semen. Prostate cancer in many cases has only mild symptoms, even without treatment. Prostate cancer can be detected by measuring concentrations of the biomarker prostate specific antigen. Its progression stage is assessed by the widely established Gleason grading scheme. In many cases it is sufficient to monitor cancer progression without treatment.
For aggressive tumors, various treatment options are available and include surgery, irradiation, cryosurgery, chemotherapy and hormonal therapy. Hormonal therapy relies on the tumor's dependence on androgen signalling, which can be ablated using the antiandrogens flutamide (CHEMBL806) and bicalutamide (CHEMBL409). However, after about two to three years, many prostate cancers become refractory to hormone therapy, even though they still rely on androgen signalling. These so-called castration resistant cancers can be treated with docetaxel (CHEMBL92) and, as a second line of defense, the newly approved Enzalutamide.

Enzalutamide and its primary metabolite N-desmethyl enzalutamide competitively inhibit androgen binding to the androgen receptor (Uniprot P10275).

Enzalutamide is a small molecule with molecular weight 464.44 and calculated logP of 3.88. It is practically insoluble in water and is administered in liquid-filled soft gelatin capsules.

IUPAC: 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5­ dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl}-2-fluoro-N-methylbenzamide
SMILES: CNC(=O)c1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C2(C)C)cc1F

Enzatulamide is administered in a daily dose of 160mg, which equates to four 40mg capsules. It has a Cmax of 16.6µg/mL that is reached after about one hour and is 97% bound to plasma proteins.

Enzatulamide is metabolised primarily by CYP2C8 (P10632) and CYP3A4 (P08684). A major metabolite, N-desmethyl enzalutamide has similar bioactivity as enzatulamide.

Adverse reactions include asthenia/fatigue, back pain, diarrhea and others.

Enzatulamide is marketed by Medivation under the trade name Xtandi.


Dave said...

I think that there is a mis-spelling just below the chemical structure: it says Enzatolamide is a small molecule.

I only bring it up as for a moment I thought that the post was talking about two different (but possibly related) compounds.

John Overington said...

Doh, thanks for spotting this.

The blog fairy has been punished!