Discovery of covalent prolyl oligopeptidase boronic ester inhibitors.

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Publisher: Elsevier B.V.
Document Type: Report; Brief article
Length: 249 words

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Keywords Prolyl oligopeptidase inhibitors; Boronic ester; Peptidomimetic; Covalent inhibitors Highlights * Potent covalent POP inhibitors were developed. * Boronic esters are acting as pro-drugs. * Computational design successfully led to potent inhibitors. * A scalable synthesis was devised. Abstract Over the past decade, many drug discovery endeavors have been invested in targeting the serine proteases prolyl oligopeptidase (POP) for the treatment of Alzheimer's and Parkinson's disease and, more recently, epithelial cancers. Our research group has focused on the discovery of reversible covalent inhibitors, namely nitriles, to target the catalytic serine residue in this enzyme. While there have been many inhibitors discovered containing a nitrile to covalently bind to the catalytic serine, we have been investigating others, particularly boronic acids and boronic esters, the latter of which have been largely unexplored as covalent warheads. Herein we report a series of computationally-designed POP boronic ester pro-drug inhibitors exhibiting nanomolar-potencies in vitro as their active boronic acid species. These easily-accessible (1--2 step syntheses) compounds could facilitate future biochemical and biological studies of this enzyme's role in neurodegenerative diseases and cancer progression. Abbreviations POP, prolyl oligopeptidase Author Affiliation: Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, QC, H3A 0B8, Canada * Corresponding author. Article History: Received 16 August 2019; Revised 9 October 2019; Accepted 10 October 2019 (footnote)1 Present Address: Naëla Janmamode, CQDM, 740 Rue Notre-Dame Ouest suite 1400, Montréal, QC H3C 3X6. Byline: Jessica Plescia, Caroline Dufresne, Naëla Janmamode (1), Alexander S. Wahba, Anthony K. Mittermaier, Nicolas Moitessier [nicolas.moitessier@mcgill.ca] (*)

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Gale Document Number: GALE|A607576600