Structure-activity relationship investigation of Phe-Arg mimetic region of human glutaminyl cyclase inhibitors. Issue 12 (23rd July 2018)

• Record Type: Journal Article
• 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
• Is Part Of: Bioorganic & medicinal chemistry. Volume 26:Issue 12(2018)
• Page Start: 3133
• Page End: 3144
• Publication Date: 2018-07-23
• Subjects: Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2018.04.040
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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 h ERG 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.