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

2018 Fiscal Year Annual Research Report

• Project/Area Number: 16F16385
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: ZHANG KAM 国立研究開発法人理化学研究所, 生命機能科学研究センター, チームリーダー (60558906)
• Co-Investigator(Kenkyū-buntansha): VIJAYAN DILEEP 国立研究開発法人理化学研究所, 生命機能科学研究センター, 外国人特別研究員
• Project Period (FY): 2016-11-07 – 2019-03-31
• Keywords: Alzheimer's disease / Glutaminyl cyclase / Drug design / Virtual screening

Outline of Annual Research Achievements

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.

Research Progress Status

平成30年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

平成30年度が最終年度であるため、記入しない。