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Discovery of Potent Human Glutaminyl Cyclase Inhibitors as Anti-Alzheimer's Agents Based on Rational Design
- Title
- Discovery of Potent Human Glutaminyl Cyclase Inhibitors as Anti-Alzheimer's Agents Based on Rational Design
- Authors
- Van-Hai Hoang; Phuong-Thao Tran; Cui, Minghua; Ngo, Van T. H.; Ann, Jihyae; Park, Jongmi; Lee, Jiyoun; Choi, Kwanghyun; Cho, Hanyang; Kim, Hee; Ha, Hee-Jin; Hong, Hyun-Seok; Cho, Sun; Kim, Young-Ho; Lee, Jeewoo
- Ewha Authors
- 최선
- SCOPUS Author ID
- 최선
- Issue Date
- 2017
- Journal Title
- JOURNAL OF MEDICINAL CHEMISTRY
- ISSN
- 0022-2623
1520-4804
- Citation
- JOURNAL OF MEDICINAL CHEMISTRY vol. 60, no. 6, pp. 2573 - 2590
- Publisher
- AMER CHEMICAL SOC
- Indexed
- SCIE; SCOPUS
- Document Type
- Article
- Abstract
- Glutaminyl cyclase (QC) has been implicated in the formation of toxic amyloid plaques by generating the N-terminal pyroglutamate of beta-amyloid peptides (pGlu-A beta) 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, A beta 3E-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 A beta and total A beta and restored cognitive functions. This potent A beta-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.
- DOI
- 10.1021/acs.jmedchem.7b00098
- Appears in Collections:
- 약학대학 > 약학과 > Journal papers
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