Potent human glutaminyl cyclase inhibitors as potential anti-Alzheimer's agents: Structure-activity relationship study of Arg-mimetic region. Issue 5 (1st March 2018)

• Record Type: Journal Article
• Authors: Ngo, Van T.H.; Hoang, Van-Hai; Tran, Phuong-Thao; Ann, Jihyae; Cui, Minghua; Park, Gyungseo; 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 5(2018)
• Page Start: 1035
• Page End: 1049
• Publication Date: 2018-03-01
• Subjects: Glutaminyl cyclase inhibitor -- Alzheimer's disease -- Beta-amyloid; 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.2018.01.015
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Pyroglutamate-modified amyloid β peptides (pGlu-Aβ) are highly neurotoxic and promote the formation of amyloid plaques. The pGlu-Aβ peptides are generated by glutaminyl cyclase (QC), and recent clinical studies indicate that QC represents an alternative therapeutic target to treat Alzheimer's disease (AD). We have previously developed a series of QC inhibitors with an extended pharmacophoric scaffold, termed the Arg-mimetic D-region. In the present study, we focused on the structure activity relationship (SAR) of analogues with modifications in the D-region and evaluated their biological activity. Most compounds in this series exhibited potent activity in vitro, and our SAR analysis and the molecular docking studies identified compound202 as a potential candidate because it forms an additional hydrophobic interaction in the h QC active site. Overall, our study provides valuable insights into the Arg-mimetic pharmacophore that will guide the design of novel QC inhibitors as potential treatments for AD.