Discovery of Potent Human Glutaminyl Cyclase Inhibitors as Anti-Alzheimer’s Agents Based on Rational Design

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

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

Glutaminyl cyclase (QC) has been implicated in the formation of toxic amyloid plaques by generating the N-terminal pyroglutamate of β-amyloid peptides (pGlu-Aβ) and thus may participate in the pathogenesis of Alzheimer’s disease (AD). We designed a library of glutamyl cyclase (QC) inhibitors based on the proposed binding mode of the preferred substrate, Aβ3E−42. An in vitro structure-activity relationship study identified several excellent QC inhibitors demonstrating 5- to 40-fold increases in potency compared to a known QC inhibitor. When tested in mouse models of AD, compound 212 significantly reduced the brain concentrations of pyroform Aβ and total Aβ and restored cognitive functions. This potent Aβ-lowering effect was achieved by incorporating an additional binding region into our previously established pharmacophoric model, resulting in strong interactions with the carboxylate group of Glu327 in the QC binding site. Our study offers useful insights in designing novel QC inhibitors as a potential treatment option for AD.

Original languageEnglish
Pages (from-to)2573-2590
Number of pages18
JournalJournal of Medicinal Chemistry
Volume60
Issue number6
DOIs
StatePublished - 23 Mar 2017

Bibliographical note

Funding Information:
This work was supported by the Korea Science and Engineering Foundation (KOSEF) grants from the Korea government (MOST) (NRF-2014M3A9D9069725) and National Leading Research Lab (NLRL) program (2011- 0028885).

Publisher Copyright:
© 2017 American Chemical Society.

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