There is a general need for new orally active androgens, to be used for androgen replacement therapy and male hormonal contraception. As a substitute for low levels of testosterone in hypogonadal men, therapy with the natural androgen testosterone is the first choice. However, testosterone is an androgen with a relatively low affinity for the androgen receptor. It is metabolically relatively unstable which results in poor oral bioavailability. In addition, testosterone is converted by

5a-reductase into the more potent androgen 5a-dihydrotestosterone (5a-DHT). Early attempts to prevent metabolic instability by 17a-alkylation of androgens (like introduction of 17 a-ethynyl in estrogens and progestagens) were not successful, due to liver toxicity or low androgenic activity (Vida 1969). Another approach to circumvent metabolic instability is esterification of the 17^-OH group of testosterone with long chain fatty acids. Testosterone undecanoate formulated in an oily solution (Andriol®/Andriol Testocaps™, dissolved in oleic acid and a mixture of castor oil and polypropylene glycol laurate, respectively) is currently the only orally active testosterone derivative. This testosterone ester is hydrolysed by tissue (liver) esterases and testosterone is released (Bursi etal. 2001). However, due to the limited potency of testosterone and limited bioavailability of testosterone undecanoate, relative high doses of Andriol®/Andriol TestocapsTM are required twice a day for human androgen replacement (total dose 160 -240 mg).

Although no side effects of testosterone replacement on the prostate have been reported, androgens which are not potentiated upon 5a-reduction in the prostate and skin, like 7a-methyl-19-nortestosterone (MENT) and 19-nortestosterone (nandrolone), are considered prostate-safe androgens (Kumar et al. 1992; Cummings et al. 1998). MENT however, has low oral activity, like testosterone, and is therefore currently being developed as a 17^-O-acetate for parenteral application.

An important metabolite of testosterone is estradiol, which is formed by the enzyme aromatase, a product of the cytochrome P450 gene family CYP19 (Simpson etal. 2002).

Since oral application is the preferred route of administration, a systematic search for more potent, metabolically stable androgens that are substrates of the aromatase enzyme, was initiated at N. V. Organon. As part of the project we investigated a series of 7a-substituted 19-nortestosterone derivatives. It was hypothesised that chain elongation and, optionally, unsaturation of the 7a-substituent (Fig. 22.1) would result in compounds with higher metabolic stability. The above mentioned androgens were characterised in vivo for their pharmacokinetic profile and their potency to suppress/prevent castration-induced LH and FSH increase, trabecular bone mineral density (BMD) loss, and the effect on prostate weight of male rats. In addition, effects on endogenous testosterone levels of intact male monkeys (Macaca arctoides) were studied. Testosterone undecanoate was used as the orally active reference androgen throughout all these in vivo studies.

Hair Loss Prevention

Hair Loss Prevention

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