新型选择性雌激素受体-β配体的设计、合成及其脑神经保护活性研究

Multiple sclerosis (MS) is a debilitating illness with high morbidity and mortality that is only poorly managed by current pharmaceuticals, with little prospects for reversing the disease. Estrogens are known to play a role in neurodegenerative diseases such as MS, and both ERα and ERβ have been studied as therapy targets. ERβ, in particular, appears to be the key mediator of a specific, autocrine anti-inflammatory pathway in microglia and astrocytes where it functions as the target for Δ5-Adiol, an endogenously produced ERβ-selective ligand. Herein we have defined brain neuroprotection as a promising, new therapeutic goal, which is accessible through ERβ without reproductive stimulation, and we are defining the particular structural characteristics of ERβ-ligands that underlie these selective actions. Thus, we are going to develop novel ERβ ligands for an important biomedical purpose: neuroprotection and reversal of neurodegeneration. Develop diverse phenolic and heterocyclic-core ligands with high ERβ selectivity and then evaluate them using discriminating in vitro and cell-based assays for anti-inflammatory activity. Evaluate the best compounds in animal models of neuroprotection and ex vivo assays of neuron function. The mechanism of these ligands with estrogen receptor β will be investigated based on structural biology and computer-aided drug design. The feasibility of these new ligands as potential drugs for MS therapy will be investigated, and their structure-activity relationship(SAR), as well as the dual mechanism of the interaction of these ligands with LBD of ERβ will also be investigated. We anticipate that based on above studies we will be able to discover a novel type of leads that have potential use as unconventional drugs or prodrugs for MS treatment.

多发性硬化症(multiple sclerosis, MS)是一种高发病率和致死率的退缩性疾病，目前很少有药物能够很好控制该疾病，而且基本不具有逆转该疾病的可能。众所周知，雌激素在神经退行性疾病如MS中扮有角色，尤其是ERβ，作为内源性雌激素ERβ选择性配体Δ5-Adiol的作用靶标，被认为是小胶质细胞和星形胶质细胞特异性自分泌抗炎通路中的一个关键调节因子。初步研究结果显示，新型、仔细发展的ERβ配体可以提供优化的抗炎活性和脑保护活性，以及可以有效逆转已发疾病病情，而对乳腺和生殖器官具有尽可能低的刺激作用，但目前具有这类活性的化合物数目有限。我们拟设计、合成系列结构多样、新颖的具有苯酚及杂环核心结构的ERβ选择性配体，研究这些配体神经保护/抗炎活性的构效关系（SAR），通过优化，进一步评价在神经退行性动物模型中的功能，以发现，尤其对已发疾病具有最强逆转活性以及最好成药活性的药物先导化合物。

雌激素在神经退行性疾病如多发性硬化症(multiple sclerosis, MS)中扮有重要角色，尤其是ERβ是小胶质细胞和星形胶质细胞特异性自分泌抗炎通路中的一个关键调节因子。已知研究表明，新型、仔细发展的ERβ配体可以提供优化的抗炎活性和脑保护活性，以及可以有效逆转已发疾病病情，而对乳腺和生殖器官具有尽可能低的刺激作用，但目前具有这类活性的化合物数目有限。本项目设计、合成了系列结构多样、新颖的具有苯酚及杂环核心结构的ERβ选择性配体，例如芳基硒酚、苯并硒唑，以及苯并呋喃酮等，活性最好的化合物对ERβ的结合亲和力约为ERα的190倍。研究了这些配体神经保护/抗炎活性的构效关系（SAR），从而有针对地对先导化合物的结构进行进一步的优化，发现了数个新型的具有神经保护/抗炎活性药物先导化合物，初步机制研究表明，部分化合物是通过激活GPER1来提供对增强胶质细胞存活的保护作用。在研期间发表SCI论文22篇，获湖北省自然科学奖三等奖1项，获批中国专利8项，取得了较为丰硕的成果。