This is a competing application to continue our studies of the pharmacology of nonsteroidal androgen receptor (AR) ligands. The long-term hypothesis of our research is that orally active nonsteroidal androgens will mimic the beneficial in vivo endocrine and pharmacologic effects of testosterone, while avoiding undesirable effects. In the first three years of this grant, we advanced our hypothesis from a set of promising in vitro data to definitive in vivo studies showing that selective androgen receptor modulators (SARMs) represent an emerging new class of therapeutic agents with potential use in most androgen-related disorders. Studies will build upon existing expertise and test 3 independent yet closely related hypotheses: 1. Hypothesis 1: Novel pharmacophores will demonstrate potent in vitro and in vivo pharmacologic effects. The SARMs discovered in our laboratories are close structural relatives of bicalutamide. This raises the question as to whether other nonsteroidal antiandrogen platforms can be structurally optimized to act as androgen agonists. These studies are a continuation of the aims of our previous grant with a refined focus on the conformational structural requirements for ligand-AR interactions. 2. Hypothesis 2: SARMs mimic the endocrine and pharmacologic effects of exogenously administered testosterone. Data presented in our progress report indicate that unique structure-activity relationships exist for regulating endocrine and testicular function. We will continue to explore this promising lead as a foray into new approach to male contraception. 3. Hypothesis 3: Steroidal and nonsteroidal androgens regulate identical gene expression patterns in the prostate, but differ in potency. Microarray studies completed in our laboratory suggest that observed differences in tissue-selectivity (i.e., the ability to maintain prostate and muscle size) are a result of differences in pharmacologic potency, tissue amplification (e.g., 5a-reductase), or drug exposure.
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