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

Publication date: 23 July 2018
Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
Author(s): 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
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.

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