Potent Human Glutaminyl Cyclase Inhibitors as Potential Anti-Alzheimer’s Agents: Structure-Activity Relationship Study of Arg-Mimetic Region

Publication date: Available online 31 January 2018
Source:Bioorganic & Medicinal Chemistry
Author(s): Van T.H. Ngo, Van-Hai Hoang, Phuong-Thao Tran, Jihyae Ann, Minghua Cui, Gyungseo Park, Sun Choi, Jiyoun Lee, Hee Kim, Hee-Jin Ha, Kwanghyun Choi, Young-Ho Kim, Jeewoo Lee
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 compound 202 as a potential candidate because it forms an additional hydrophobic interaction in the hQC 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.

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