Small molecule antiandrogens that are available today have undesirable side effects caused by complete, non-selective inhibition of AR action. To minimize these side effects, a new class of tissue selective androgen receptor modulators (SARMs) has been proposed as a novel approach for the treatment of prostate cancer. These ligands should behave as antagonists in the prostate with either no activity or agonist activity in other target tissues, so as to have little or no effects in the anabolic tissues or central nervous system (CNS). However discovering this new class of ligands might be challenging because the molecular mechanism of AR action is not well understood.
Several mechanisms have been proposed to achieve this tissue selectivity of AR ligands. The most definitive evidence exists for the role of 5-alpha reductase. 5-alpha reductase is only expressed in specific tissues and could therefore be a unique contributor to tissue selectivity. Specific inhibition of the type 2 enzyme by finasteride blocks the conversion of testosterone to DHT in the prostate.
Several approaches might make use of the potential tissue-specific conversion to develop SARMs, including:
# Inactive parent compounds that are activated by type 2 5-alpha reductase in the prostate to form antiandrogens.
# AR agonists that are inactivated by type 2 5-alpha reductase in the prostate.
#  AR agonists that are converted to antiandrogens only by type 2 5-alpha reductase in the prostate.