Novel progestogenic androgens for male contraception: design, synthesis, and activity of C7 -substituted testosterone

Male contraceptive development has included use of testosterone (T) with or without a progestin or the use of a single molecule such as progestogenic androgens (PA) for suppression of testicular T production. Expanding upon the vast amount of data accumulated from nortestosterone (NT), NT analogs, and their prodrugs, a new series of PA, the C7 methyl, and ethyl alpha-substituted T analogs 7 alpha-Methyltestosterone (7 alpha-MT) and 7 alpha-Ethyltestosterone (7 alpha-ET), respectively, were hypothesized and designed to have superior androgenic and progestogenic activities when compared with parent T. Results from androgen receptor and progesterone receptor competitive binding and transcriptional activation assays showed favorable activities for these T analogs. Additionally, 7 alpha-MT and 7 alpha-ET were shown to be active substrates for aromatase in vitro, mitigating a potential negative impact on bone mineral density with long-term use. In conjunction with this observation, the diminished metabolism of these T analogs by 5 alpha-reductase may reduce potential concerns for prostatic growth. In the Hershberger in vivo rat bioassay, 7 alpha-MT and 7 alpha-ET showed superior androgenic and anabolic activities as compared with T. These C7 alpha-substituted T analogs also showed clear progestogenic activity in the McPhail bioassay which evaluated endometrial glandular arborization in a rabbit model. The discovery of aromatizable molecules with reduced metabolism by 5 alpha-reductase that have androgenic, anabolic, and progestogenic properties indicates that the core and/or prodrugs of 7 alpha-MT and 7 alpha-ET are promising molecules for further development as male contraceptive PAs.