Potent human glutaminyl cyclase inhibitors as potential anti-Alzheimer's agents: Structure-activity relationship study of Arg-mimetic region
- 주제(키워드) Alzheimer's disease , Beta-amyloid , Glutaminyl cyclase inhibitor
- 등재 SCIE, SCOPUS
- 발행기관 Elsevier Ltd
- 발행년도 2018
- URI http://www.dcollection.net/handler/ewha/000000150090
- 본문언어 영어
- Published As http://dx.doi.org/10.1016/j.bmc.2018.01.015
초록/요약
Pyroglutamate-modified amyloid β peptides (pGlu-Aβ) are highly neurotoxic and promote the formation of amyloid plaques. The pGlu-Aβ peptides are generated by glutaminyl cyclase (QC), and recent clinical studies indicate that QC represents an alternative therapeutic target to treat Alzheimer's disease (AD). We have previously developed a series of QC inhibitors with an extended pharmacophoric scaffold, termed the Arg-mimetic D-region. In the present study, we focused on the structure activity relationship (SAR) of analogues with modifications in the D-region and evaluated their biological activity. Most compounds in this series exhibited potent activity in vitro, and our SAR analysis and the molecular docking studies identified compound 202 as a potential candidate because it forms an additional hydrophobic interaction in the hQC active site. Overall, our study provides valuable insights into the Arg-mimetic pharmacophore that will guide the design of novel QC inhibitors as potential treatments for AD. © 2018 Elsevier Ltd
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