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

人谷氨酰环酶是介导pGlu-Aβ多肽形成的重要酶，因此被认为是治疗阿尔茨海默病(AD)药物的潜在靶点。在我们的研究中，已经采取了一种努力来确定潜在的HQC抑制剂。已经确定了两种潜在的HQC抑制剂，它们具有纳米摩尔抑制能力。进行了基于结构的设计，合成了16个类似物。他们的酶试验已经针对HQC进行了。研究表明，除了两个分子外，所有的类似物都表现出非常有前途的活性(都是在纳米摩尔抑制中)。测定了它们的共晶结构，研究了它们的构效关系。对这些化合物的血脑屏障通透性也进行了研究。其中一些化合物表现出良好的血脑屏障渗透性。目前正在进行这些化合物的离解常数和细胞毒性分析。测定了两种H3R拮抗剂氯苯丙特和硫代巴比妥钠的IC50值。这些化合物表现出中等的抗HQC活性。此外，还在原子分辨下确定了这些化合物与HQC的共晶结构。这些研究将有助于多靶点定向配体的设计。

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.