Androgen receptor modulators: a review of recent patents and reports (2012-2018)

Androgen receptor (AR) is one of the most promising targets of drug discovery because of its importance in male reproductive systems and homeostasis of bone and muscle. Various AR-modulating agents have been developed and used clinically to treat androgen-dependent disorders, including prostate cancer, and some new-generation antiandrogens have recently been approved. Intensive studies are underway to develop various AR-modulating compounds, including conventional antagonists, tissue-specific AR modulators (SARMs), degraders, and nonconventional AR-modulating compounds that target sites other than the ligand-binding domain (LBD), such as the N-terminal domain (NTD) or the DNA-binding domain (DBD).

The authors provide an overview of AR-modulating agents from 2012 to 2018.

The LBD has been the primary target for AR modulation, and important AR-modulating agents, including SARMs and recently approved antiandrogens such as enzalutamide and apalutamide, have been developed as conventional LBD antagonists. Development of LBD-targeting antiandrogens to treat prostate cancer is a kind of cat-and-mouse game between clinical agents and AR mutations, and therefore next-generation antiandrogens are still required. Development of nonconventional AR-modulating agents targeting NTD and DBD, is likely to be a promising approach to develop multiple and synergistic strategies able to overcome any kind of androgen-dependent condition.