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Extended Structure–Activity Relationship and Pharmacokinetic Investigation of (4-Quinolinoyl)glycyl-2-cyanopyrrolidine Inhibitors of Fibroblast Activation Protein (FAP)
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    Extended Structure–Activity Relationship and Pharmacokinetic Investigation of (4-Quinolinoyl)glycyl-2-cyanopyrrolidine Inhibitors of Fibroblast Activation Protein (FAP)
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    Medicinal Chemistry, Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium
    Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, Pennsylvania 19111-2497, United States
    § Laboratory of Microbiology, Parasitology, and Hygiene, Departments of Pharmaceutical Sciences and Biomedical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium
    Medical Biochemistry, Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium
    *E-mail: [email protected]. Phone: +32-3 265 27 08.
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2014, 57, 7, 3053–3074
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    https://doi.org/10.1021/jm500031w
    Published March 11, 2014
    Copyright © 2014 American Chemical Society

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    Fibroblast activation protein (FAP) is a serine protease related to dipeptidyl peptidase IV (DPPIV). It has been convincingly linked to multiple disease states involving remodeling of the extracellular matrix. FAP inhibition is investigated as a therapeutic option for several of these diseases, with most attention so far devoted to oncology applications. We previously discovered the N-4-quinolinoyl-Gly-(2S)-cyanoPro scaffold as a possible entry to highly potent and selective FAP inhibitors. In the present study, we explore in detail the structure–activity relationship around this core scaffold. We report extensively optimized compounds that display low nanomolar inhibitory potency and high selectivity against the related dipeptidyl peptidases (DPPs) DPPIV, DPP9, DPPII, and prolyl oligopeptidase (PREP). The log D values, plasma stabilities, and microsomal stabilities of selected compounds were found to be highly satisfactory. Pharmacokinetic evaluation in mice of selected inhibitors demonstrated high oral bioavailability, plasma half-life, and the potential to selectively and completely inhibit FAP in vivo.

    Copyright © 2014 American Chemical Society

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    Detailed synthetic procedures and analytical data for intermediates, protocols of the enzymatic assays used, and procedures and extended data series for in vitro and in vivo pharmacokinetic analyses. This material is available free of charge via the Internet at http://pubs.acs.org.

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    Cite this: J. Med. Chem. 2014, 57, 7, 3053–3074
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    Published March 11, 2014
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