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

Van T.H. Ngo, Van Hai Hoang, Phuong Thao Tran, Nguyen Van Manh, Jihyae Ann, Eunhye Kim, Minghua Cui, Sun Choi, Jiyoun Lee, Hee Kim, Hee Jin Ha, Kwanghyun Choi, Young Ho Kim, Jeewoo Lee

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

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.

Original languageEnglish
Pages (from-to)3133-3144
Number of pages12
JournalBioorganic and Medicinal Chemistry
Volume26
Issue number12
DOIs
StatePublished - 23 Jul 2018

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