Studies on Aromatase Inhibitors. I. 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 synthesized 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 electron-withdrawing group on the phenyl moiety, showed potent aromatase-inhibitory activity. Structure-activity relationship studies indicated that 4-[(4-bromobenzyl)(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 nM in in vitro experiments using rat ovary and human placenta, respectively, and an in vivo ED50of 0.002 mg/kg in rats on oral administration.YM511 was also a weak inhibitor of other steroid hormone synthesis enzymes. These data suggest that YM511 is a highly selective aromatase inhibitor and may be a useful agent for the treatment of estrogen-dependent diseases such as breast cancer.