| 研究実績の概要 |
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.
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