Synthesis, biological evaluation, and molecular modeling of abiraterone analogues: novel CYP17 inhibitors for the treatment of prostate cancer.

Article Details

Citation

Copy to clipboard

Pinto-Bazurco Mendieta MA, Negri M, Jagusch C, Muller-Vieira U, Lauterbach T, Hartmann RW

Synthesis, biological evaluation, and molecular modeling of abiraterone analogues: novel CYP17 inhibitors for the treatment of prostate cancer.

J Med Chem. 2008 Aug 28;51(16):5009-18. doi: 10.1021/jm800355c. Epub 2008 Aug 2.

PubMed ID

18672868 [ View in PubMed

]

Abstract

Abiraterone, a steroidal cytochrome P450 17alpha-hydroxylase-17,20-lyase inhibitor (CYP17), is currently undergoing phase II clinical trials as a potential drug for the treatment of androgen-dependent prostate cancer. Since steroidal compounds often show side effects attributable to their structure, we have tried to replace the sterane scaffold by nonsteroidal core structures. The design and synthesis of 20 new abiraterone mimetics are described. Their activities have been tested with recombinant human CYP17 expressed in E. coli. Promising compounds were further evaluated for selectivity against CYP11B1, CYP11B2, and the hepatic CYP3A4. Compounds 19 and 20 showed comparable activity to abiraterone (IC50 values of 144 and 64 nM vs 72 nM) and similar or even better selectivity against the other CYP enzymes. Selected compounds were also docked into our homology model, and the same binding modes as for abiraterone were found.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Abiraterone	Cytochrome P450 3A4	IC 50 (nM)	2704	7.4	37	Details
Abiraterone	Steroid 17-alpha-hydroxylase/17,20 lyase	IC 50 (nM)	72	7.4	37	Details
Ketoconazole	Cytochrome P450 3A4	IC 50 (nM)	72	7.4	37	Details