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Potent human glutaminyl cyclase inhibitors as potential anti-Alzheimer's agents: Structure-activity relationship study of Arg-mimetic region
- Potent human glutaminyl cyclase inhibitors as potential anti-Alzheimer's agents: Structure-activity relationship study of Arg-mimetic region
- Ngo, Van T. H.; Van-Hai Hoang; Phuong-Thao Tran; Ann, Jihyae; Cui, Minghua; Park, Gyungseo; Choi, Sun; Lee, Jiyoun; Kim, Hee; Ha, Hee-Jin; Choi, Kwanghyun; Kim, Young-Ho; Lee, Jeewoo
- Ewha Authors
- SCOPUS Author ID
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- Journal Title
- BIOORGANIC & MEDICINAL CHEMISTRY
- BIOORGANIC & MEDICINAL CHEMISTRY vol. 26, no. 5, pp. 1035 - 1049
- Glutaminyl cyclase inhibitor; Alzheimer's disease; Beta-amyloid
- PERGAMON-ELSEVIER SCIENCE LTD
- SCI; SCIE; SCOPUS
- Document Type
- Pyroglutamate-modified amyloid beta peptides (pGlu-A beta) are highly neurotoxic and promote the formation of amyloid plaques. The pGlu-A beta 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. (C) 2018 Elsevier Ltd. All rights reserved.
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