高选择性α1D/1A亚型阻断剂AW03类似物的设计、合成及其生物活性研究

α1肾上腺素受体阻断剂为治疗前列腺增生症（BPH）的一线用药，而现有临床药物对其三种亚型（α1A、α1B、α1D）缺乏选择性，存在严重副作用。研究表明，α1A、α1D亚型为有效作用靶标，α1D/1A阻断剂优于单一的α1A阻断剂和无亚型选择性药物。我们课题组研发的萘哌地尔是临床上仅有的α1D/1A阻断剂药物，但经研究发现仍存在亚型选择性不高、活性作用不强和生物利用度低等问题。经过多年的结构优化，我们已确立了更高选择性的苗头化合物AW03，它对α1D、α1A的选择性是对α1B的97.7倍和64.6倍，能选择性降低尿道压，但对α1D、α1A的阻断活性仍未显著提高。在此基础上，本项目拟设计、合成AW03类似物，从细胞、离体组织功能研究其生物活性和亚型选择性，考察其生物利用度，采用尿生殖窦大鼠体内模型验证其抗BPH作用，以期获得具有应用前景的候选物，并揭示其构效关系，为开发新一代药物提供科学依据。

α1 adrenergic receptor blocker is the first-line drug for the treatment of benign prostatic hyperplasia (BPH), however, the existing clinical drugs have serious side effects due to lacking the selectivity of three subtypes (α1A, α1B, and α1D). Studies have shown that α1A and α1D subtypes are the effective targets, α1D/1A blocker is better than that of single α1A blocker and no subtype selective drug. Naftopidil is the only α1D/1A blocker in clinic, developed by our team. It has some problems such as low subtype selectivity, low activity and low bioavailability. After years of structural optimization, we have established a hit compound AW03 with higher subtype selectivity. The effect of AW03 on α1D and α1A is 97.7 and 64.6 folder higher than that of α1B; high uro-selectivity is also exhibited. However, the blocking activity on α1D and α1A still needs to be improved. On this basis, this project intends to design and synthesize AW03 analogues. New compounds will be evaluated for their biological activity and subtype selectivity by cellular high throughput screening and isolated tissues functional assays, calculating the bioavailability, and then will be evaluated for.anti BPH effect by urogenital sinus rat models, in order to obtain candidate compounds with application prospect. The structure-activity relationship will also be revealed to provide scientific basis for further research of new generation drugs.