Δ⁴-Abiraterone

Δ⁴-Abiraterone (D4A; code name CB-7627), also known as 17-(3-pyridyl)androsta-4,16-dien-3-one, is a steroidogenesis inhibitor and active metabolite of abiraterone acetate, a drug which is used in the treatment of prostate cancer and is itself a prodrug of abiraterone (another active metabolite of abiraterone acetate).[1] D4A is formed from abiraterone by 3β-hydroxysteroid dehydrogenase/Δ^5-4 isomerase (3β-HSD).[1] It is said to be a more potent inhibitor of steroidogenesis than abiraterone, and is partially responsible for the activity of abiraterone acetate.[1]

Δ⁴-Abiraterone

Clinical data
Other names	D4A; CB-7627; 17-(3-Pyridyl)androsta-4,16-dien-3-one
Identifiers
IUPAC name (8R,9S,10R,13S,14S)-10,13-Dimethyl-17-pyridin-3-yl-1,2,6,7,8,9,11,12,14,15-decahydrocyclopenta[a]phenanthren-3-one
CAS Number	154229-21-7
PubChem CID	196941
ChemSpider	170572
CompTox Dashboard (EPA)	DTXSID90934961
Chemical and physical data
Formula	C24H29NO
Molar mass	347.502 g·mol^−1
3D model (JSmol)	Interactive image
SMILES C[C@]12CCC(=O)C=C1CC[C@@H]3[C@@H]2CC[C@]4([C@H]3CC=C4C5=CN=CC=C5)C
InChI InChI=1S/C24H29NO/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/h3-4,7,13-15,19,21-22H,5-6,8-12H2,1-2H3/t19-,21-,22-,23-,24+/m0/s1 Key:GYJZZAJJENTSTP-NHFPKVKZSA-N

D4A is specifically an inhibitor of CYP17A1 (17α-hydroxylase/17,20-lyase), 3β-HSD, and 5α-reductase.[1] In addition, it has also been found to act as a competitive antagonist of the androgen receptor (AR), with potency reportedly comparable to that of enzalutamide.[1] However, the initial 5α-reduced metabolite of D4A, 3-keto-5α-abiraterone, is an agonist of the AR, and has been found to stimulate prostate cancer progression.[2] The formation of this metabolite can be blocked by the coadministration of dutasteride, a selective and highly potent 5α-reductase inhibitor, and the addition of this medication may improve the effectiveness of abiraterone acetate in the treatment of prostate cancer.[2]

References

1. Li Z, Bishop AC, Alyamani M, Garcia JA, Dreicer R, Bunch D, Liu J, Upadhyay SK, Auchus RJ, Sharifi N (July 2015). "Conversion of abiraterone to D4A drives anti-tumour activity in prostate cancer". Nature. 523 (7560): 347–51. doi:10.1038/nature14406. PMC 4506215. PMID 26030522.
2. Li Z, Alyamani M, Li J, Rogacki K, Abazeed M, Upadhyay SK, Balk SP, Taplin ME, Auchus RJ, Sharifi N (May 2016). "Redirecting abiraterone metabolism to fine-tune prostate cancer anti-androgen therapy" (PDF). Nature. 533 (7604): 547–51. doi:10.1038/nature17954. PMC 5111629. PMID 27225130.