Loading…

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

[Display omitted] 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 dev...

Full description

Saved in:
Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2018-07, Vol.26 (12), p.3133-3144
Main Authors: Ngo, Van T.H., Hoang, Van-Hai, Tran, Phuong-Thao, Van Manh, Nguyen, Ann, Jihyae, Kim, Eunhye, Cui, Minghua, Choi, Sun, Lee, Jiyoun, Kim, Hee, Ha, Hee-Jin, Choi, Kwanghyun, Kim, Young-Ho, Lee, Jeewoo
Format: Article
Language:English
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:[Display omitted] 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.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2018.04.040