Novel oestrogen sulfamates: a new approach to oral hormone therapy

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Abstract
Sulfamate substitution at the C-3 position of the steroid skeleton leads to orally active prodrugs of ethinyloestradiol, oestradiol, oestrone, oestriol and probably many other natural or synthetic steroidal oestrogens. These compounds have higher systemic, but reduced hepatic, oestrogenic activity than their parent steroids. The release of the parent oestrogen results from the passage of the sulfamates in the erythrocyte compartment through the liver and the systemic hydrolysis of the sulfamate ester. Sulfamates may be used to generate natural oestrogens, oestradiol and other oestrogens for different types of oral oestrogen therapy, e.g., as oestriol for hindered oestrogen or as 17-alpha oestradiol for 'non-feminising' oestrogen. Oestradiol sulfamate J995 is currently in the initial stages of clinical testing. It has per se no oestrogen receptor affinity or oestrogenic activity in vitro, i.e., is inactive without hydrolysis. Its oral uterotropic activity in rats is approximately 100-times higher than that of oestradiol, its hepatotropic activity, however, is only 2- to 3-fold higher than oestradiol. Oral oestradiol sulfamate treatment should, therefore, reduce the hepatic side-effects seen with conventional oral hormone therapy, while at the same time lead to full stimulation of the uterus and the vagina, and suppression of gonadotropin. In the rat, orally administered oestradiol is effectively extracted from the portal vein and excreted via the bile. In contrast, oestradiol sulfamate is present in the circulation at high concentrations, up to 30% of the dose. Initially, 98% of this is found in the erythrocyte compartment and only 2% in the plasma. Significant oestradiol levels in the blood are recorded during the depletion of this pool. Pharmacokinetic and toxicological studies reveal complete excretion of the compound and its metabolites. No toxic effects have been seen in rats and cynomolgus monkeys at any dose, in spite of the compound's distinct oestrogenicity. The evaluation of genotoxicity also yielded negative results.