Pharmacology of nonsteroidal androgen receptor ligands

描述(由申请人提供)：这是一个竞争性的申请，以继续我们的非类固醇雄激素受体(AR)配体的药理学研究。我们研究的长期假设是，口服活性的非类固醇雄激素将模仿睾酮在体内有益的内分泌和药理作用，同时避免不良影响。在这笔赠款的前三年，我们将我们的假设从一组有希望的体外数据发展到明确的体内研究，表明选择性雄激素受体调节剂(SARM)代表了一种新兴的治疗药物，具有潜在的治疗大多数雄激素相关疾病的作用。研究将建立在现有专业知识的基础上，并测试3个独立但密切相关的假说：1.假说1：新的药效团将在体外和体内显示出强大的药理作用。在我们实验室中发现的SARM是比卡鲁胺的结构上的近亲。这提出了一个问题，即其他非类固醇抗雄激素平台是否可以在结构上进行优化，以作为雄激素激动剂。这些研究是我们之前资助的目标的继续，重点是配体-AR相互作用的构象结构要求。2.假设2：SARMS模拟外源性注射睾酮的内分泌和药理作用。我们的进展报告中提供的数据表明，存在着调节内分泌和睾丸功能的独特结构-活性关系。我们将继续探索这一有希望的线索，作为对男性避孕新方法的尝试。3.假设3：类固醇和非类固醇雄激素调节前列腺中相同的基因表达模式，但效力不同。在我们实验室完成的微阵列研究表明，观察到的组织选择性(即维持前列腺和肌肉大小的能力)的差异是由于药物效力、组织扩增(例如5a-还原酶)或药物暴露的差异造成的。

DESCRIPTION (provided by applicant): 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.