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Discovery of potent human glutaminyl cyclase inhibitors as anti-alzheimers agents based on rational design
DC Field | Value | Language |
---|---|---|
dc.contributor.author | Van-Hai Hoang | - |
dc.contributor.author | Phuong-Thao Tran | - |
dc.contributor.author | Cui, Minghua | - |
dc.contributor.author | Ngo, Van T. H. | - |
dc.contributor.author | Ann, Jihyae | - |
dc.contributor.author | Park, Jongmi | - |
dc.contributor.author | Lee, Jiyoun | - |
dc.contributor.author | Choi, Kwanghyun | - |
dc.contributor.author | Cho, Hanyang | - |
dc.contributor.author | Kim, Hee | - |
dc.contributor.author | Ha, Hee-Jin | - |
dc.contributor.author | Hong, Hyun-Seok | - |
dc.contributor.author | Cho, Sun | - |
dc.contributor.author | Kim, Young-Ho | - |
dc.contributor.author | Lee, Jeewoo | - |
dc.creator | 이지우 | - |
dc.date.accessioned | 2019-04-25T02:05:00Z | - |
dc.date.available | 2020-04-05T02:05:00Z | - |
dc.date.created | 2017-11-15 | - |
dc.date.created | 2017-11-15 | - |
dc.date.issued | 2017-03 | - |
dc.identifier.citation | Journal of Medicinal Chemistry, Vol.60 No.6, pp.2573-2590 | - |
dc.identifier.issn | 0022-2623 | - |
dc.identifier.uri | https://hdl.handle.net/10371/150130 | - |
dc.description.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. | - |
dc.language | 영어 | - |
dc.language.iso | en | en |
dc.publisher | American Chemical Society | - |
dc.title | Discovery of potent human glutaminyl cyclase inhibitors as anti-alzheimers agents based on rational design | - |
dc.type | Article | - |
dc.identifier.doi | 10.1021/acs.jmedchem.7b00098 | - |
dc.citation.journaltitle | Journal of Medicinal Chemistry | - |
dc.identifier.wosid | 000397546000029 | - |
dc.identifier.scopusid | 2-s2.0-85016278636 | - |
dc.description.srnd | OAIID:RECH_ACHV_DSTSH_NO:T201724898 | - |
dc.description.srnd | RECH_ACHV_FG:RR00200001 | - |
dc.description.srnd | ADJUST_YN: | - |
dc.description.srnd | EMP_ID:A003772 | - |
dc.description.srnd | CITE_RATE:6.253 | - |
dc.description.srnd | DEPT_NM:약학과 | - |
dc.description.srnd | EMAIL:jeewoo@snu.ac.kr | - |
dc.description.srnd | SCOPUS_YN:Y | - |
dc.citation.endpage | 2590 | - |
dc.citation.number | 6 | - |
dc.citation.startpage | 2573 | - |
dc.citation.volume | 60 | - |
dc.description.isOpenAccess | N | - |
dc.contributor.affiliatedAuthor | Lee, Jeewoo | - |
dc.identifier.srnd | T201724898 | - |
dc.type.docType | Article | - |
dc.description.journalClass | 1 | - |
dc.subject.keywordPlus | AMYLOID BETA-PEPTIDES | - |
dc.subject.keywordPlus | A-BETA | - |
dc.subject.keywordPlus | DISEASE | - |
dc.subject.keywordPlus | PROTEIN | - |
dc.subject.keywordPlus | NEURODEGENERATION | - |
dc.subject.keywordPlus | HYPOTHESIS | - |
dc.subject.keywordPlus | DEPOSITION | - |
dc.subject.keywordPlus | EXPRESSION | - |
dc.subject.keywordPlus | PITUITARY | - |
dc.subject.keywordPlus | PLAQUES | - |
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