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Discovery of Potent Human Glutaminyl Cyclase Inhibitors as Anti-Alzheimer’s Agents Based on Rational Design
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    Discovery of Potent Human Glutaminyl Cyclase Inhibitors as Anti-Alzheimer’s Agents Based on Rational Design
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    Laboratory of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
    National Leading Research Laboratory of Molecular Modeling & Drug Design, College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea
    § Medifron DBT, Sandanro 349, Danwon-Gu, Ansan-City, Gyeonggi-Do 15426, Republic of Korea
    Department of Global Medical Science, Sungshin University, Seoul 01133, Republic of Korea
    Department of Pharmaceutical Chemistry, Hanoi University of Pharmacy, Hanoi, Vietnam
    *Phone: 82-2-880-7846. Fax: 82-2-888-0649. E-mail: [email protected]
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2017, 60, 6, 2573–2590
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    https://doi.org/10.1021/acs.jmedchem.7b00098
    Published February 24, 2017
    Copyright © 2017 American Chemical Society

    Abstract

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    Glutaminyl cyclase (QC) has been implicated in the formation of toxic amyloid plaques by generating the N-terminal pyroglutamate of β-amyloid peptides (pGlu-Aβ) and thus may participate in the pathogenesis of Alzheimer’s disease (AD). We designed a library of glutamyl cyclase (QC) inhibitors based on the proposed binding mode of the preferred substrate, Aβ3E−42. An in vitro structure–activity relationship study identified several excellent QC inhibitors demonstrating 5- to 40-fold increases in potency compared to a known QC inhibitor. When tested in mouse models of AD, compound 212 significantly reduced the brain concentrations of pyroform Aβ and total Aβ and restored cognitive functions. This potent Aβ-lowering effect was achieved by incorporating an additional binding region into our previously established pharmacophoric model, resulting in strong interactions with the carboxylate group of Glu327 in the QC binding site. Our study offers useful insights in designing novel QC inhibitors as a potential treatment option for AD.

    Copyright © 2017 American Chemical Society

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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2017, 60, 6, 2573–2590
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jmedchem.7b00098
    Published February 24, 2017
    Copyright © 2017 American Chemical Society

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