Development of novel androgen receptor antagonists based on the structure of darolutamide

Androgen signaling pathway plays an important role in the occurrence and development of prostate cancer (PCa), and anti-androgen drugs are one of the most effective therapies for PCa. Darolutamide 4 (ODM-201) is a promising second-generation antiandrogen because of its unique chemical structure and good activity against androgen receptor (AR). Herein, the structure-activity relationship of ODM-201 was studied, and 37 analogues were synthesized. Half of them exhibited similar or better anti-AR transcriptional activity compared to ODM-201. In addition, the inhibitory activity of compound 28t against the two resistant mutants (AR-F876L and AR-T877A) was superior to that of ODM-201. This study provides a new clue for the further optimization of ODM-201 and the development of anti-CRPC drugs.

Automated summary

The androgen signaling pathway is crucial in prostate cancer (PCa), and the anti-androgen drug Darolutamide (ODM-201) shows promising activity against the androgen receptor. This study synthesized 37 analogues of ODM-201 with half of them exhibiting similar or better anti-AR transcriptional activity, and compound 28t showed superior inhibitory activity against resistant mutants.