title: Acylated Gly-(2-cyano)pyrrolidines as inhibitors of fibroblast activation protein (FAP) and the issue of FAP/prolyl oligopeptidase (PREP)-selectivity.
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.
authors.affiliation: Medicinal Chemistry (UAMC), Department of Pharmaceutical Sciences, University of Antwerp (UA), Antwerp, Belgium.
authors.forename: Oxana
authors.initials: O
authors.lastname: Ryabtsova
authors.forename: Koen
authors.initials: K
authors.lastname: Jansen
authors.forename: Sebastiaan
authors.initials: S
authors.lastname: Van Goethem
authors.forename: Jurgen
authors.initials: J
authors.lastname: Joossens
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Cheng
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Lambeir
authors.forename: Ingrid
authors.initials: I
authors.lastname: De Meester
authors.forename: Koen
authors.initials: K
authors.lastname: Augustyns
authors.forename: Pieter
authors.initials: P
authors.lastname: Van der Veken
mesh_terms: D000215:Acylation; D010450:Endopeptidases; D018093:Gelatinases / Q000037:antagonists & inhibitors*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D000085822:Prolyl Oligopeptidases; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology*; D012697:Serine Endopeptidases / Q000378:metabolism*; D013329:Structure-Activity Relationship; D000099167:Fibroblast Activation Protein Alpha
chemical_list: D010450:Endopeptidases; D018093:Gelatinases; D008565:Membrane Proteins; D000085822:Prolyl Oligopeptidases; D011759:Pyrrolidines; D012697:Serine Endopeptidases; D000099167:Fibroblast Activation Protein Alpha