STUDIES ON AROMATASE INHIBITORS .1. SYNTHESIS AND BIOLOGICAL EVALUATION OF 4-AMINO-4H-1,2,4-TRIAZOLE DERIVATIVES

Various 4-N-substituted amino-4H-1,2,4-triazole derivatives were synth esized and evaluated for aromatase-inhibitory activity (in vitro) and for pregnant mare serum gonadotropin (PMSG)-induced estrogen synthesis -inhibitory activity (in vivo). The 4-(4-cyanophenyl) amino derivative and 4-(4-nitrophenyl)amino derivative, each possessing a strong elect ron-withdrawing group on the phenyl moiety, showed potent aromatase-in hibitory activity. Structure-activity relationship studies indicated t hat romobenzyl)(4-cyanophenyl)amino]-4H-1,2,4-triazole (5k, YM511) is a highly potent aromatase inhibitor with IC50 values of 0.4 and 0.12 n M in in vitro experiments using rat ovary and human placenta, respecti vely, and an in vivo ED(50) of 0.002 mg/kg in rats on oral administrat ion. YM511 was also a weak inhibitor of other steroid hormone synthesi s enzymes. These data suggest that YM511 is a highly selective aromata se inhibitor and may be a useful agent for the treatment of estrogen-d ependent diseases such as breast cancer.