选择性α1A肾上腺素受体拮抗剂的设计、合成及抗前列腺增生药理活性研究

Benign prostatic hyperplasia (BPH) is one of the most common diseases of middle and old aged men, the voiding symptoms caused by BPH seriously affect the health and quality of life of patients. Selective α1A-adrenoceptor antagonists are the most effective and most frequently used anti-BPH agents which cause the lowest side effects. However, there are only two drugs, namely tamsulosin and silodosin, were marketed as selective α1A-adrenoceptor antagonists. It is worth noting that these two drugs also cause obvious and serious side effects in clinic. In our previous research, two lead compounds, (R)-A18 and (R)-B12, which can significantly improve the voiding symptoms of BPH rats were identified by conducting structural modification of silodosin. In this program, we plan to conduct systematical structural modification and structure-activity relationship research of (R)-A18 and (R)-B12. This project aims to discover lead compounds with better efficacy and lower side effects than silodosin, excellent pharmacokinetic properties and safety through a series of biological evaluations, such as calcium assays, functional assays with isolated rat tissues, micturition behavior studies in BPH model rats, cardiovascular side effects studies in dogs, retrograde ejaculation side effects studies in rats, pharmacokinetic evaluation and preliminary safety evaluation.

良性前列腺增生(BPH)是中老年男性常见疾病之一，其引起的排尿困难等症状严重影响患者的身体健康和生活质量。选择性α1A肾上腺素受体(α1A-AR)拮抗剂是目前治疗BPH最有效的药物，也是最常用、副作用最小的药物，然而目前只有两个选择性α1A-AR拮抗剂即坦索罗辛和西洛多辛上市。值得注意的是，它们在临床上都存在明显且较严重的副作用。在前期研究中，我们对西洛多辛进行结构改造并发现了能显著改善BPH模型大鼠排尿症状的先导化合物(R)-A18和(R)-B12。本项目拟对前期发现的先导化合物(R)-A18和(R)-B12展开系统的结构改造和构效关系研究，并旨在通过细胞及离体组织上的活性和选择性评价、BPH模型大鼠体内药效评价、犬心血管方面的副作用评价、大鼠射精障碍副作用评价、药物代谢动力学评价和初步安全性评价从而发现药效比西洛多辛更好、副作用比西洛多辛更小、药物代谢性质优良、安全性高的先导化合物。