title: Extended structure-activity relationship and pharmacokinetic investigation of (4-quinolinoyl)glycyl-2-cyanopyrrolidine inhibitors of fibroblast activation protein (FAP).
abstract: 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.
authors.affiliation: Medicinal Chemistry, Department of Pharmaceutical Sciences, University of Antwerp , Universiteitsplein 1, B-2610 Antwerp, Belgium.
authors.forename: Koen
authors.initials: K
authors.lastname: Jansen
authors.forename: Leen
authors.initials: L
authors.lastname: Heirbaut
authors.forename: Robert
authors.initials: R
authors.lastname: Verkerk
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Cheng
authors.forename: Jurgen
authors.initials: J
authors.lastname: Joossens
authors.forename: Paul
authors.initials: P
authors.lastname: Cos
authors.forename: Louis
authors.initials: L
authors.lastname: Maes
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: D000818:Animals; D001682:Biological Availability; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D010450:Endopeptidases; D018093:Gelatinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008861:Microsomes / Q000187:drug effects*; D015394:Molecular Structure; D010949:Plasma / Q000737:chemistry*; D011759:Pyrrolidines / Q000737:chemistry*; D012697:Serine Endopeptidases / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D000099167:Fibroblast Activation Protein Alpha
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D010450:Endopeptidases; D018093:Gelatinases; D008565:Membrane Proteins; D011759:Pyrrolidines; D012697:Serine Endopeptidases; D000099167:Fibroblast Activation Protein Alpha