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Structure-activity relationship investigation of Phe-Arg mimetic region of human glutaminyl cyclase inhibitors

Title
Structure-activity relationship investigation of Phe-Arg mimetic region of human glutaminyl cyclase inhibitors
Authors
Ngo V.T.H.Hoang V.-H.Tran P.-T.Van Manh N.Ann J.Kim E.Cui M.Choi S.Lee J.Kim H.Ha H.-J.Choi K.Kim Y.-H.
Ewha Authors
최선
SCOPUS Author ID
최선scopus
Issue Date
2018
Journal Title
Bioorganic and Medicinal Chemistry
ISSN
0968-0896JCR Link
Citation
Bioorganic and Medicinal Chemistry vol. 26, no. 12, pp. 3133 - 3144
Publisher
Elsevier Ltd
Indexed
SCI; SCIE; SCOPUS WOS scopus
Document Type
Article
Abstract
Glutamyl cyclase (QC) is a promising therapeutic target because of its involvement in the pathogenesis of Alzheimer's disease. In this study, we developed novel QC inhibitors that contain 3-aminoalkyloxy-4-methoxyphenyl and 4-aminoalkyloxyphenyl groups to replace the previously developed pharmacophore. Several potent inhibitors were identified, showing IC50 values in a low nanomolar range, and were further studied for in vitro toxicity and in vivo activity. Among these, inhibitors 51 and 53 displayed the most potent AβN3pE−40-lowering effects in in vivo acute model with reasonable BBB penetration, without showing cytotoxicity and hERG inhibition. The molecular modeling analysis of 53 indicated that the salt bridge interaction and the hydrogen bonding in the active site provided a high potency. Given the potent activity and favorable BBB penetration with low cytotoxicity, we believe that compound 53 may serve as a potential candidate for anti-Alzheimer's agents. © 2018 Elsevier Ltd
DOI
10.1016/j.bmc.2018.04.040
Appears in Collections:
약학대학 > 약학과 > Journal papers
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