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Discovery and Therapeutic Promise of Selective Androgen Receptor Modulators for Hormonal Male Contraception

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2005, Doctor of Philosophy, Ohio State University, Pharmacy.
There is an urgent need to develop new forms of contraception that men are willing to use. Currently, testosterone-based hormonal contraceptives represent the most promising approach. However, testosterone demonstrates little activity after oral administration due to rapid hepatic elimination, precluding its use in oral contraceptives for men. The long-term safety of testosterone, as it relates to psychological function, cardiovascular disease, and prostate disease, is also of concern. Non-steroidal selective androgen receptor modulators (SARMs) may provide an alternative to the use of testosterone, with the advantages of oral bioavailability, tissue selectivity, lack of influence on lipoproteins, and androgen receptor (AR) specificity. We hypothesized that SARMs would mimic the pharmacologic activity of testosterone in vivo and can safely replace testosterone as a component of hormonal male contraceptives. SARMs discovered previously demonstrated potential applications in the treatment of muscle wasting, osteoporosis, and benign prostate hyperplasia in animal models. However, low or no CNS effects were observed, which precluded their use for hormonal male contraception as a single regimen. Novel AR ligands were designed and synthesized using integrated knowledge of molecular modeling, structure-activity-relationships, and pharmacokinetics and metabolism of known SARMs. In the current studies, the abilities of these compounds to bind AR and to stimulate (agonist) or inhibit (antagonist) AR-mediated transcriptional activation (Chapter 2) were determined. Compounds with high AR binding affinity and potent stimulatory activity in transcriptional assays were further investigated in castrated rats (Chapter 3) for their pharmacologic effects. Key in vitro and in vivo structure-activity-relationships of these ligands were identified. Differences in the pharmacokinetics and metabolism between SARMs resulted in a contradiction between the in vitro and in vivo pharmacologic activity, and also provided rationale for further structural modifications (Chapter 4). Through our iterative, step-wise experimental paradigm, more potent SARMs were discovered using structural modifications of our lead compound. The effects of the potent SARMs on spermatogenesis, reproductive and peripheral organs, body composition, hormonal biomarkers, sexual behavior, and fertility were further investigated (Chapters 5 through 7). As a whole, these studies provide valuable information regarding the physiologic and pharmacokinetic factors governing the pharmacology and feasibility of SARMs for hormonal male contraception.
James Dalton (Advisor)

Recommended Citations

Citations

  • Chen, J. (2005). Discovery and Therapeutic Promise of Selective Androgen Receptor Modulators for Hormonal Male Contraception [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1117548610

    APA Style (7th edition)

  • Chen, Jiyun. Discovery and Therapeutic Promise of Selective Androgen Receptor Modulators for Hormonal Male Contraception. 2005. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1117548610.

    MLA Style (8th edition)

  • Chen, Jiyun. "Discovery and Therapeutic Promise of Selective Androgen Receptor Modulators for Hormonal Male Contraception." Doctoral dissertation, Ohio State University, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=osu1117548610

    Chicago Manual of Style (17th edition)