jm9b00751_si_002.csv (3.54 kB)
Download fileDiscovery of Conformationally Restricted Human Glutaminyl Cyclase Inhibitors as Potent Anti-Alzheimer’s Agents by Structure-Based Design
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posted on 2019-08-27, 16:41 authored by 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, Jeewoo LeeAlzheimer’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.
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nonrestricted analoguesprototype inhibitor 1AD mouse modelQC inhibitionN-substituted thiourearepresentative inhibitoramide derivativesalternative targetsneurodegenerative diseaseconformationAD patientsConformationally Restricted Human Glutaminyl Cyclase Inhibitorsalternative approachesβ- amyloidglutaminyl cyclase