Discovery of Conformationally Restricted Human Glutaminyl Cyclase Inhibitors as Potent Anti-Alzheimer's Agents by Structure-Based Design

Van Hai Hoang, Van T.H. Ngo, Minghua Cui, Nguyen Van Manh, Phuong Thao Tran, Jihyae Ann, Hee Jin Ha, Hee Kim, Kwanghyun Choi, Young Ho Kim, Hyerim Chang, Stephani Joy Y. MacAlino, Jiyoun Lee, Sun Choi

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Alzheimer's disease (AD) is an incurable, progressive neurodegenerative disease whose pathogenesis cannot be defined by one single element but consists of various factors; thus, there is a call for alternative approaches to tackle the multifaceted aspects of AD. Among the potential alternative targets, we aim to focus on glutaminyl cyclase (QC), which reduces the toxic pyroform of β-amyloid in the brains of AD patients. On the basis of a putative active conformation of the prototype inhibitor 1, a series of N-substituted thiourea, urea, and α-substituted amide derivatives were developed. The structure-activity relationship analyses indicated that conformationally restrained inhibitors demonstrated much improved QC inhibition in vitro compared to nonrestricted analogues, and several selected compounds demonstrated desirable therapeutic activity in an AD mouse model. The conformational analysis of a representative inhibitor indicated that the inhibitor appeared to maintain the Z-E conformation at the active site, as it is critical for its potent activity.

Original languageEnglish
Pages (from-to)8011-8027
Number of pages17
JournalJournal of Medicinal Chemistry
Volume62
Issue number17
DOIs
StatePublished - 12 Sep 2019

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