Pharmacology of Nonsteroidal Androgen Receptor Ligands

非甾体雄激素受体配体的药理学

• 批准号: 6382029
• 负责人: JAMES T DALTON
• 金额: $ 22.4万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6382029
• 关键词: androgen analog; androgen receptor; chemical structure function; corticosteroid receptors; drug design /synthesis /production; estrogen receptors; laboratory rat; ligands; male; pharmacokinetics; progesterone receptors; receptor binding; transcription factor

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.

在我们的实验室研究寻找亲电子亲和配体的雄激素受体（AR），我们发现，已知的非甾体类抗雄激素的结构修饰的结果在雄激素活性。这些化合物代表了一类新的雄激素药物，并且是第一个报道的非甾体AR激动剂。其他人最近证实了非甾体配体刺激AR介导的转录的能力。基于最近报道的结构-活性关系和我们在非甾体AR配体的结合、药理学和药代动力学方面的经验，本文提出的研究是该领域研究的关键延伸。我们的研究分为三个独立的努力：1。非甾体类AR配体的设计、合成及新型AR配体。我们合成了一系列比卡鲁胺类似物，其以高亲和力结合AR并诱导雄激素受体介导的转录激活。我们在此提出了一个合理的药物设计和有机合成的其他非甾体雄激素的基础上，文献数据和初步数据，在我们的实验室。2. AR的体外功能活性和特异性。我们将研究AR结合亲和力和AR介导的转录激活潜在的非甾体雄激素在细胞转染的人。AR.评价这些药物的一个关键因素是区分AR和其他类固醇受体，如糖皮质激素（GR），孕酮（PR）和雌激素受体（ER）的能力。全细胞结合实验和转录激活研究将在用GR、PR. ER和AR检测受体特异性。3.整个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中刺激雄激素介导的生长的能力。我们将在去势和完整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根据这些药物的理化和药代动力学特性建立构效关系。