Pharmacological characterization of a novel oestrogen antagonist, ZK 119010, in rats and mice.

The oestrogenic and antioestrogenic effects of a new nonsteroidal compound ZK 119010 (2-(4-hydroxyphenyl)-3-methyl-1-[6-(1-pyrrolidinyl)-hexyl]-indol-5-ol) were evaluated and compared with those of tamoxifen and ICI 164384. In immature mice, ZK 119010 administered once daily for 3 days (s.c.) inhibited the uterotrophic and vaginotrophic effect of oestradiol in a dose-dependent manner and was distinctly more potent than tamoxifen or ICI 164384 in exerting antioestrogenic effects. When antioestrogens in combination with oestradiol were administered once daily for 5 days to ovariectomized adult rats, ZK 119010 at lower doses (less than or equal to 1 mg/kg) was slightly less effective than tamoxifen in inhibiting the uterotrophic effect of oestradiol. At the higher doses, however, ZK 119010 was strongly antioestrogenic, and ICI 164384 was less effective than ZK 119010 or tamoxifen. ZK 119010 at 10 mg/kg, like ICI 164384 at 30 mg/kg, caused an almost complete inhibition of the oestradiol-induced uterine growth in rats. The antioestrogenic effect of tamoxifen in rats was also limited by its inherent oestrogenic property. The oestrogenic activity of ZK 119010 was much below that of tamoxifen, whereas ICI 164384 did not show oestrogenicity. The present results indicate that ZK 119010 is a novel type of non-steroidal antioestrogen which has only a marginal oestrogenic effect in rats and mice. Such an antioestrogen may be useful for the treatment of oestrogen-sensitive diseases in man.