During studies in our laboratory to search for electrophilic affinity ligands for the androgen receptor (AR), we discovered that structural modification of known non-steroidal anti-androgens results in androgenic activity. These compounds represents a new class of androgenic drugs, and were the first reported non-steroidal AR agonists. Others have recently confirmed the ability of non-steroidal ligands to stimulate AR- mediated transcription. The studies proposed herein are a pivotal extension of research in this field based on recently reported structure- activity relationships and our experience binding, pharmacology, and pharmacokinetics of non-steroidal AR ligands. Our studies are divided into three independent efforts: 1. Design and Synthesis and Novel Non-steroidal AR Ligands. We synthesized a series of bicalutamide analogs that bind the AR with high affinity and induce androgen receptor-mediated transcriptional activation. We proposed herein a strategy for rational drug design and organic syntheses of additional non-steroidal androgens based on literature data and preliminary data obtained in our laboratories. 2. In Vitro Functional Activity and Specificity for AR. We will examine AR binding affinity and AR-mediated transcriptional activation of potential non-steroidal androgens in cells transfected with the human. AR. A key element in evaluation of these drugs will be the ability to discriminate between AR and other steroid receptors, such as glucocorticoid (GR), progesterone (PR) and estrogen receptors (ER). Whole cell binding experiments and transcriptional activation studies will be conducted in cells transfected with the GR, PR., ER and AR to examine receptor specificity. 3. Androgenic and Anabolic Activity in Whole Animals. The utility of these compounds is ultimately dependent on their ability to stimulate androgen-mediated growth in whole animals. We will conduct integrated pharmacokinetic and efficacy studies in castrated and intact male rats to determine the in vivo pharmacologic activity, bioavailability, and pharmacokinetics of these drugs. The overall goal of these studies is to develop structure-activity relationships based on the physicochemical and pharmacokinetic properties of these drugs.
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