Pharmacology of Nonsteroidal Androgen Receptor Ligands

在我们实验室寻找雄激素受体（AR）的亲电亲和配体的研究中，我们发现已知的非甾体抗雄激素的结构修饰会导致雄激素活性。这些化合物代表了一类新的雄激素药物，是首次报道的非甾体类AR激动剂。其他人最近证实了非甾体配体刺激AR介导转录的能力。本文提出的研究是基于最近报道的结构-活性关系以及我们对非甾体AR配体的结合、药理学和药代动力学的经验的研究的关键延伸。我们的研究分为三个独立的努力：1。新型非甾体AR配体的设计与合成。我们合成了一系列高亲和力结合AR的比卡鲁胺类似物，并诱导雄激素受体介导的转录激活。在此，我们根据文献数据和实验室获得的初步数据，提出了合理的药物设计和有机合成其他非甾体雄激素的策略。2. AR的体外功能活性和特异性。我们将在转染人的细胞中检测AR结合亲和力和AR介导的潜在非甾体雄激素的转录激活。AR：评估这些药物的一个关键因素将是区分AR和其他类固醇受体的能力，如糖皮质激素（GR）、孕激素（PR）和雌激素受体（ER）。将在转染GR、PR、ER和AR的细胞中进行全细胞结合实验和转录激活研究，以检验受体特异性。3. 全动物的雄激素和合成代谢活性。这些化合物的效用最终取决于它们在整个动物体内刺激雄激素介导的生长的能力。我们将在阉割和完整的雄性大鼠中进行综合药代动力学和疗效研究，以确定这些药物的体内药理学活性、生物利用度和药代动力学。这些研究的总体目标是在这些药物的物理化学和药代动力学性质的基础上发展结构-活性关系。

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.