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Discovery of Conformationally Restricted Human Glutaminyl Cyclase Inhibitors as Potent Anti-Alzheimer's Agents by Structure-Based Design
- Title
- Discovery of Conformationally Restricted Human Glutaminyl Cyclase Inhibitors as Potent Anti-Alzheimer's Agents by Structure-Based Design
- Authors
- Van-Hai Hoang; Ngo, Van T. H.; Cui, Minghua; Nguyen Van Manh; Phuong-Thao Tran; Ann, Jihyae; Ha, Hee-Jin; Kim, Hee; Choi, Kwanghyun; Kim, Young-Ho; Chang, Hyerim; Macalino, Stephani Joy Y.; Lee, Jiyoun; Choi, Sun; Lee, Jeewoo
- Ewha Authors
- 최선
- SCOPUS Author ID
- 최선
- Issue Date
- 2019
- Journal Title
- JOURNAL OF MEDICINAL CHEMISTRY
- ISSN
- 0022-2623
1520-4804
- Citation
- JOURNAL OF MEDICINAL CHEMISTRY vol. 62, no. 17, pp. 8011 - 8027
- Publisher
- AMER CHEMICAL SOC
- Indexed
- SCIE; SCOPUS
- Document Type
- Article
- 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 beta-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 alpha-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.
- DOI
- 10.1021/acs.jmedchem.9b00751
- Appears in Collections:
- 약학대학 > 약학과 > Journal papers
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