title: Potent and selective aromatase inhibitor: in vitro and in vivo studies with s-triazine derivative SEF19.
abstract: We found a potent aromatase inhibitor through the screening of agents for estrogen-dependent breast cancer. SEF19 (2-(imidazol-1-yl)-4,6-dimorphorino-1,3,5-triazine) decreased 50% of human placental aromatase activity in vitro at the concentration of 5.3 nM. In order to clarify the selectivity of SEF19 for enzyme inhibition, we determined the effect of SEF19 on the activities of four steroidogenic cytochrome P450 enzymes in porcine adrenal gland, P450SCC(side-chain cleavage of cholesterol), P450(11 beta) (11 beta-hydroxylase), P450(17 alpha)(17 alpha-hydroxylase/C17,20 lyase) and P450C21 (21-hydroxylase). SEF19 failed to inhibit the activities of porcine adrenal P450SCC, P450(17 alpha) and P450C21 up to the concentration of 100 microM and showed some inhibition on P450(11 beta) activity at 100 microM, while SEF19 completely nullified the aromatase activity at 1 microM. We also determined the potency of SEF19 for the suppression of aromatase activity in vivo. SEF19 suppressed dose-dependently the uterine hypertrophy of immature rats caused by administration of androstenedione (30 mg/kg, s.c.). The ED50 of SEF19 for the suppression of uterine hypertrophy was 0.8 mumol/kg. These results suggest that SEF19 may serve as a potent and selective agent for the treatment of estrogen-dependent breast cancer.
authors.affiliation: Research Laboratory, Zenyaku Kogyo Co., Ltd., Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Takahashi
authors.forename: T
authors.initials: T
authors.lastname: Kayo
authors.forename: T
authors.initials: T
authors.lastname: Karakida
authors.forename: S
authors.initials: S
authors.lastname: Nakagawa
authors.forename: M
authors.initials: M
authors.lastname: Kato
authors.forename: S
authors.initials: S
authors.lastname: Matsuno
authors.forename: Y
authors.initials: Y
authors.lastname: Koide
authors.forename: M
authors.initials: M
authors.lastname: Sakato
authors.forename: S
authors.initials: S
authors.lastname: Kawashima
mesh_terms: D000735:Androstenedione / Q000494:pharmacology; D000818:Animals; D047072:Aromatase Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D017316:Fadrozole / Q000494:pharmacology*; D005260:Female; D006801:Humans; D006984:Hypertrophy / Q000473:pathology; D007093:Imidazoles / Q000494:pharmacology*; D010920:Placenta / Q000187:drug effects* / Q000201:enzymology; D051381:Rats; D017208:Rats, Wistar; D014227:Triazines / Q000494:pharmacology*; D014599:Uterus / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology
chemical_list: C107532:2-(imidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine; D047072:Aromatase Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007093:Imidazoles; D014227:Triazines; D000735:Androstenedione; D017316:Fadrozole