Highly selective inhibition of estrogen biosynthesis by CGS 20267, a new non-steroidal aromatase inhibitor.

CGS 20267 is a new non-steroidal compound which potently inhibits aromatase in vitro (IC50 of 11.5 nM) and in vivo (ED50 of 1-3 micrograms/kg p.o.), CGS 20267 maximally inhibits estradiol production in vitro in LH-stimulated hamster ovarian tissue at 0.1 microM with an IC50 of 0.02 microM and does not significantly affect progesterone production up to 350 microM. In ACTH-stimulated rat adrenal tissue in vitro, aldosterone production was inhibited with an IC50 of 210 microM (10,000 times higher than the IC50 for estradiol production); no significant effect on corticosterone production was seen at 350 microM. In vivo, in ACTH-treated rats, CGS 20267 does not affect plasma levels of corticosterone or aldosterone at a dose of 4 mg/kg p.o. (1000 times higher than the ED50 for aromatase inhibition in vivo). In adult female rats, a 14-day treatment with 1 mg/kg p.o. daily, completely interrupts ovarian cyclicity and suppresses uterine weight to that seen 14 days after ovariectomy. In adult female rats bearing estrogen-dependent DMBA-induced mammary tumors, 0.1 mg/kg p.o. given daily for 42 days caused almost complete regression of tumors present at the start of treatment. Thus compared to each other, CGS 16949A and CGS 20267 are both highly potent in inhibiting estrogen biosynthesis in vitro and in vivo. The striking difference between them is that unlike CGS 16949A, CGS 20267 does not affect adrenal steroidogenesis in vitro or in vivo, at concentrations and doses several orders of magnitude higher than those required to inhibit estrogen biosynthesis.