Novel dehydroepiandrosterone analogues with enhanced biological activity and reduced side effects in mice and rats.

Treatment of laboratory mice and rats with the adrenal steroid, dehydroepiandrosterone (DHEA), produces antiobesity and broad spectrum tumor chemopreventive activity. Certain side effects are associated with DHEA administration which could limit its usefulness as a drug. DHEA can be metabolized into both testosterone and estrone and also increases liver weight and liver catalase activity. We have developed two synthetic steroids, 16 alpha-fluoro-5-androstan-17-one and 16 alpha-fluoro-5 alpha-androstan-17-one, which, unlike DHEA, do not stimulate uterine weight in sexually immature female rats or seminal vesicle weight in castrated male rats, nor stimulate liver weight and liver catalase activity in mice. 16 alpha-Fluoro-5-androsten-17-one is also about three times as potent as DHEA as an antiobesity agent and is more active when administered p.o. in inhibiting [3H]-7,12-dimethylbenz(a)-anthracene binding to skin DNA and tetradecanoylphorbol-13-acetate stimulation of epidermal [3H]thymidine incorporation in the mouse, two effects believed to be important in the tumor preventive action of DHEA. 16 alpha-Fluoro-5 alpha-androstan-17-one is as active as 16 alpha-fluoro-5-androsten-17-one in inhibiting [3H]-7,12-dimethylbenz(a)anthracene binding to skin DNA and tetradecanoylphorbol-13-acetate stimulation in epidermal [3H]thymidine incorporation but, on the contrary, is not more active than DHEA as an antiobesity drug. Compounds such as 16 alpha-fluoro-5-androsten-17-one and 16 alpha-fluoro-5 alpha-androstan-17-one, which lack specific side-effects of DHEA treatment and demonstrate greater potency, may have therapeutic application as drugs for humans.