Androgen receptor antagonists (antiandrogens): Structure-activity relationships

Prostate cancer, acne, seborrhea, hirsutism, and androgenic alopecia are we ll recognized to depend upon an excess or increased sensitivity to androgen s or to be at least sensitive to androgens. It thus seems logical to use an tiandrogens as therapeutic agents to prevent androgens from binding to the androgen receptor. The two predominant naturally occurring androgens are te stosterone (T) and dihydrotestosterone. (DHT). DHT is the more potent andro gen in vivo and in vitro. All androgen-responsive genes are activated by an drogen receptor (AR) bound to either T or DHT and it is believed that AR is more transcriptionally active when bound to DHT than T. The two classes of antiandrogens, presently available, are the steroidal derivatives, all of which possess mixed agonistic and antagonistic activities, and the pure non -steroidal antiandrogens of the class of flutamide and its derivatives. The intrinsic androgenic, estrogenic and glucocorticoid activities of steroida l derivatives have limited their use in the treatment of prostate cancer. T he non-steroidal flutamide and its derivatives display pure antiandrogenic activity, without exerting agonistic or any other hormonal activity. Flutam ide (89) and its derivatives, Casodex (108) and Anandron (114), are highly effective in the treatment of prostate cancer. The combination of flutamide and Anandron with castration has shown prolongation of life in prostate ca ncer. Furthermore, combined androgen blockade in association with radical p rostatectomy or radiotherapy are very effective in the treatment of localiz ed prostate cancer. Such an approach certainly raises the hope of a further improvement in prostate cancer therapy. However, all antiandrogens, develo ped so-far display moderate affinity for the androgen receptor, and thus mo derate efficacy in vitro and in vivo. There is thus a need for next-generat ion antiandrogens, which could display an equal or even higher affinity for AR compared to the natural androgens, and at the same time maintain its pu re antiandrogenic activity, and thus providing improved androgen blockade u sing possibly antiandrogens alone.