- N-substituted thiourea or urea derivatives and pharmaceutical composition for use in preventing or treating glutaminyl cyclase activity related diseases containing the same as an active ingredient
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The N - substituted thiourea or urea derivative and the pharmaceutical composition for preventing or treating glutaminyl cyclase (QC) activity containing the same as an active ingredient. The phenylthiourea derivative according to the present invention bi
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Paragraph 0245-0248; 0250-0253; 0296-0300; 0494-0499
(2021/02/02)
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- Discovery of Conformationally Restricted Human Glutaminyl Cyclase Inhibitors as Potent Anti-Alzheimer's Agents by Structure-Based Design
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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.
- Hoang, Van-Hai,Ngo, Van T.H.,Cui, Minghua,Manh, Nguyen Van,Tran, Phuong-Thao,Ann, Jihyae,Ha, Hee-Jin,Kim, Hee,Choi, Kwanghyun,Kim, Young-Ho,Chang, Hyerim,MacAlino, Stephani Joy Y.,Lee, Jiyoun,Choi, Sun
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p. 8011 - 8027
(2019/10/11)
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