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Ryabtsova O , Jansen K , Van Goethem S , Joossens J , Cheng JD , Lambeir AM , De Meester I , Augustyns K , Van der Veken P
Acylated Gly-(2-cyano)pyrrolidines as inhibitors of fibroblast activation protein (FAP) and the issue of FAP/prolyl oligopeptidase (PREP)-selectivity
Bioorg Med Chem Lett. 2012 May 15;22(10) :3412-7
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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.
Ryabtsova, Oxana Jansen, Koen Van Goethem, Sebastiaan Joossens, Jurgen Cheng, Jonathan D Lambeir, Anne-Marie De Meester, Ingrid Augustyns, Koen Van der Veken, Pieter eng Research Support, Non-U.S. Gov't England Bioorg Med Chem Lett. 2012 May 15;22(10):3412-7. doi: 10.1016/j.bmcl.2012.03.107. Epub 2012 Apr 4.