Pharmacology of nonsteroidal androgen receptor ligands

描述（由申请人提供）：这是一项竞争性申请，旨在继续我们的非甾体雄激素受体（AR）配体药理学研究。我们研究的长期假设是口服活性非甾体雄激素将模拟睾酮的有益体内内分泌和药理学作用，同时避免不良反应。在这项资助的前三年，我们将我们的假设从一组有希望的体外数据推进到确定的体内研究，表明选择性雄激素受体调节剂（SARM）代表了一类新兴的治疗药物，在大多数雄激素相关疾病中具有潜在的用途。研究将建立在现有的专业知识和测试3个独立但密切相关的假设：1。假设1：新的药效团将在体外和体内表现出有效的药理作用。在我们的实验室中发现的SARM是比卡鲁胺的结构近亲。这就提出了一个问题，即其他非甾体抗雄激素平台是否可以在结构上优化，以作为雄激素激动剂。这些研究是我们以前资助的目标的延续，重点关注配体-AR相互作用的构象结构要求。 2.假设2：SARM模拟外源性睾酮的内分泌和药理作用。我们的进展报告中的数据表明，存在独特的结构-活性关系，用于调节内分泌和睾丸功能。我们将继续探索这一有希望的领先优势，作为男性避孕新方法的一次尝试。 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差异（即，维持前列腺和肌肉大小的能力）是药理学效力，组织扩增（例如，5 α-还原酶）或药物暴露。

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.