P2-Substituted N-Acylprolylpyrrolidine Inhibitors of Prolyl Oligopeptidase: Biochemical Evaluation, Binding Mode Determination, and Assessment in a Cellular Model of Synucleinopathy

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• 作者：Pieter Van der Veken ; Vilmos F眉l枚p ; Dean Rea ; Melanie Gerard ; Roos Van Elzen ; Jurgen Joossens ; Jonathan D. Cheng ; Veerle Baekelandt ; Ingrid De Meester ; Anne-Marie Lambeir ; Koen Augustyns
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：November 26, 2012
• 年：2012
• 卷：55
• 期：22
• 页码：9856-9867
• 全文大小：765K
• 年卷期：v.55,no.22(November 26, 2012)
• ISSN：1520-4804

文摘

We have investigated the effect of regiospecifically introducing substituents in the P2 part of the typical dipeptide derived basic structure of PREP inhibitors. This hitherto unexplored modification type can be used to improve target affinity, selectivity, and physicochemical parameters in drug discovery programs focusing on PREP inhibitors. Biochemical evaluation of the produced inhibitors identified several substituent types that significantly increase target affinity, thereby reducing the need for an electrophilic 鈥渨arhead鈥?functionality. Pronounced PREP specificity within the group of Clan SC proteases was generally observed. Omission of the P1 electrophilic function did not affect the overall binding mode of three representative compounds, as studied by X-ray crystallography, while the P2 substituents were demonstrated to be accommodated in a cavity of PREP that, to date, has not been probed by inhibitors. Finally, we report on results of selected inhibitors in a SH-SY5Y cellular model of synucleinopathy and demonstrate a significant antiaggregation effect on 伪-synuclein.