Acylated Gly-(2-cyano)pyrrolidines as inhibitors of fibroblast activation protein (FAP) and the issue of FAP/prolyl oligopeptidase (PREP)-selectivity

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Abstract

A series of N-acylated glycyl-(2-cyano)pyrrolidines were synthesized with the aim of generating structure–activity relationship (SAR) data for this class of compounds as inhibitors of fibroblast activation protein (FAP). Specifically, the influence of (1) the choice of the N-acyl group and (2) structural modification of the 2-cyanopyrrolidine residue were investigated. The inhibitors displayed inhibitory potency in the micromolar to nanomolar range and showed good to excellent selectivity with respect to the proline selective dipeptidyl peptidases (DPPs) DPP IV, DPP9 and DPP II. Additionally, selectivity for FAP with respect to prolyl oligopeptidase (PREP) is reported. Not unexpectedly, the latter data suggest significant overlap in the pharmacophoric features that define FAP or PREP-inhibitory activity and underscore the importance of systematically evaluating the FAP/PREP-selectivity index for inhibitors of either of these two enzymes. Finally, this study forwards several compounds that can serve as leads or prototypic structures for future FAP-selective-inhibitor discovery.

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Acknowledgments

This work was financially supported by the Fund for Scientific Research Flanders/FWO-Vlaanderen (A.M.L., I.D.M.) the BOF-fund of the University of Antwerp (O.R., K.J., I.D.M., K.A., P.V.d.V.) and the Hercules Foundation. We are indebted to Nicole Lamoen and Willy Bollaert for excellent technical assistance.

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