Potent human glutaminyl cyclase inhibitors as potential anti-Alzheimer's agents: Structure-activity relationship study of Arg-mimetic region

Van T.H. Ngo, Van Hai Hoang, Phuong Thao Tran, Jihyae Ann, Minghua Cui, Gyungseo Park, Sun Choi, Jiyoun Lee, Hee Kim, Hee Jin Ha, Kwanghyun Choi, Young Ho Kim, Jeewoo Lee

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1035-1049
Number of pages15
JournalBioorganic and Medicinal Chemistry
Volume26
Issue number5
DOIs
StatePublished - 1 Mar 2018

Keywords

  • Alzheimer's disease
  • Beta-amyloid
  • Glutaminyl cyclase inhibitor

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