Discovery of human Glutaminyl Cyclase inhibitors for the treatment of Alzheimer's disease

人谷氨酸环化酶（hQC）是介导pGlu-Aβ肽形成的重要酶，因此被认为是抗阿尔茨海默病（AD）药物开发的潜在靶点。在我们的研究中，已努力鉴定针对hQC的潜在抑制剂。已经鉴定了两种具有纳摩尔抑制能力的hQC潜在抑制剂。基于结构设计，合成了16个类似物。已针对hQC进行了其酶促测定。研究表明，除两个分子外，所有类似物都表现出相当有希望的活性（均为纳米摩尔抑制）。测定了它们的共晶结构，研究了它们的构效关系。还进行了这些化合物的血脑屏障渗透性。一些化合物表现出有希望的血脑屏障渗透性。目前正在进行这些化合物的解离常数和细胞毒性分析。测定了氯苄丙酸和硫哌丁胺两种H_3R拮抗剂的IC_（50）值。这些化合物对hQC表现出中等活性。此外，这些化合物与hQC的共晶结构也在原子分辨率下确定。这些研究为多靶点定向配体的设计提供了理论依据。

Human glutaminyl cyclase (hQC) is an important enzyme which mediates the formation of pGlu-Aβ peptides and hence it has been considered as a potential target for the drug discovery against Alzheimer’s disease (AD). In our studies an effort has been taken to identify potential inhibitors against hQC. Two potential inhibitors of hQC have been identified with nano-molar inhibition capacity. Structure based design has been carried out and 16 analogues of these compounds were synthesized. Their enzymatic assay has been carried out against hQC. The studies suggested that all of the analogues exhibited quite promising activities (all in nano molar inhibition) except two molecules. Their co-crystal structures were determined and structure activity relationship has been studied. The blood brain barrier permeability of these compounds has also been carried out. A few of the compounds exhibited promising BBB penetrability. The dissociation constants and cytotoxicity profiling of these compounds are currently being carried out. The IC50 values of two H3R antagonists such as clobenpropit and thioperamide have been determined. These compounds exhibited moderate activities against hQC. Furthermore, the co-crystal structures of these compounds with hQC were also determined at atomic resolution. The studies will be beneficial for the designing of multi-target directed ligands.