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J Med Chem. 2017 Aug 10;60(15):6664-6677. doi: 10.1021/acs.jmedchem.7b00648. Epub 2017 Jul 25.

Synthesis and Evaluation of Diphenyl Conjugated Imidazole Derivatives as Potential Glutaminyl Cyclase Inhibitors for Treatment of Alzheimer's Disease.

Li M1,2, Dong Y1,2, Yu X1,2, Li Y1, Zou Y2, Zheng Y2, He Z1, Liu Z3, Quan J4, Bu X5, Wu H1,2,6.

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Department of Pharmacy, School of Medicine, Shenzhen University , Shenzhen 518060, China.
College of Life Sciences and Oceanography, Shenzhen University , Shenzhen 518060, China.
School of Medicine, Shenzhen University , Shenzhen 518060, China.
Key Laboratory of Structural Biology, School of Chemical Biology & Biotechnology, Peking University, Shenzhen Graduate School , Shenzhen 518055, China.
School of Pharmaceutical Science, Sun Yat-sen University , Guangzhou, 510006, China.
Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, California 90095, United States.


High expression of glutaminyl cyclase (QC) contributes to the initiation of Alzheimer's disease (AD) by catalyzing the generation of neurotoxic pyroglutamate (pE)-modified β-amyloid (Aβ) peptides. Preventing the generation of pE-Aβs by QC inhibition has been suggested as a novel approach to a disease-modifying therapy for AD. In this work, a series of diphenyl conjugated imidazole derivatives (DPCIs) was rationally designed and synthesized. Analogues with this scaffold exhibited potent inhibitory activity against human QC (hQC) and good in vitro blood-brain barrier (BBB) permeability. Further assessments corroborated that the selected hQC inhibitor 28 inhibits the activity of hQC, dramatically reduces the generation of pE-Aβs in cultured cells and in vivo, and improves the behavior of AD mice.

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