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P2-substitutedN-acylprolylpyrrolidine inhibitors of prolyl oligopeptidase : biochemical evaluation, binding mode determination, and assessment in a cellular model of synucleinopathy
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Van der Veken, Pieter, Fülöp, Vilmos, Rea, Dean, Gerard, Melanie, Van Elzen, Roos, Joossens, Jurgen, Cheng, Jonathan D., Baekelandt, Veerle, De Meester, Ingrid, Lambeir, Anne-Marie and Augustyns, Koen (2012) P2-substitutedN-acylprolylpyrrolidine inhibitors of prolyl oligopeptidase : biochemical evaluation, binding mode determination, and assessment in a cellular model of synucleinopathy. Journal of Medicinal Chemistry, Vol.55 (No.22). pp. 9856-9867. doi:10.1021/jm301060g ISSN 0022-2623.
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Official URL: http://dx.doi.org/10.1021/jm301060g
Abstract
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 “warhead” 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 α-synuclein.
Item Type: | Journal Article | ||||
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Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) | ||||
Journal or Publication Title: | Journal of Medicinal Chemistry | ||||
Publisher: | American Chemical Society | ||||
ISSN: | 0022-2623 | ||||
Official Date: | 2012 | ||||
Dates: |
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Volume: | Vol.55 | ||||
Number: | No.22 | ||||
Page Range: | pp. 9856-9867 | ||||
DOI: | 10.1021/jm301060g | ||||
Status: | Peer Reviewed | ||||
Publication Status: | Published | ||||
Access rights to Published version: | Restricted or Subscription Access |
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