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 ED50 of 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.
Okada
M
M
Endocrinology/Metabolic Disease Laboratories, Yamanouchi Pharmaceutical Co., Ltd., Tsukuha, Japan.
Yoden
T
T
Kawaminami
E
E
Shimada
Y
Y
Kudoh
M
M
Isomura
Y
Y
Shikama
H
H
Fujikura
T
T
D000450:Aldosterone / Q000096:biosynthesis; D000818:Animals; D047072:Aromatase Inhibitors; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004967:Estrogens / Q000097:blood; D005260:Female; D006064:Gonadotropins, Equine / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D011247:Pregnancy; D011817:Rabbits; D051381:Rats; D013256:Steroids / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000494:pharmacology
D047072:Aromatase Inhibitors; D004791:Enzyme Inhibitors; D004967:Estrogens; D006064:Gonadotropins, Equine; D013256:Steroids; D014230:Triazoles; C096486:YM 511; D000450:Aldosterone