Δ⁴-Abiraterone

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;

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]

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

^ ^a ^b ^c ^d ^e 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. Bibcode:2015Natur.523..347L. doi:10.1038/nature14406. PMC 4506215. PMID 26030522.
^ ^a ^b 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. Bibcode:2016Natur.533..547L. doi:10.1038/nature17954. PMC 5111629. PMID 27225130.

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[LiBishop2015-1] 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. Bibcode:2015Natur.523..347L. doi:10.1038/nature14406. PMC 4506215. PMID 26030522.

[LiAlyamani2016-2] 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. Bibcode:2016Natur.533..547L. doi:10.1038/nature17954. PMC 5111629. PMID 27225130.

[1]

[2]

Δ4-Abiraterone

References

Δ⁴-Abiraterone