Extended structure-activity relationship and pharmacokinetic investigation of (4-quinolinoyl)glycyl-2-cyanopyrrolidine inhibitors of fibroblast activation protein (FAP)

J Med Chem. 2014 Apr 10;57(7):3053-74. doi: 10.1021/jm500031w. Epub 2014 Mar 24.


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.

MeSH terms

  • Animals
  • Biological Availability
  • Dipeptidyl-Peptidase IV Inhibitors / administration & dosage
  • Dipeptidyl-Peptidase IV Inhibitors / pharmacokinetics
  • Dipeptidyl-Peptidase IV Inhibitors / pharmacology*
  • Endopeptidases
  • Gelatinases / antagonists & inhibitors*
  • Gelatinases / metabolism
  • Humans
  • Membrane Proteins / antagonists & inhibitors*
  • Membrane Proteins / metabolism
  • Mice
  • Microsomes / drug effects*
  • Molecular Structure
  • Plasma / chemistry*
  • Pyrrolidines / chemistry*
  • Serine Endopeptidases / metabolism
  • Spectrometry, Mass, Electrospray Ionization
  • Structure-Activity Relationship
  • Tissue Distribution


  • Dipeptidyl-Peptidase IV Inhibitors
  • Membrane Proteins
  • Pyrrolidines
  • Endopeptidases
  • Serine Endopeptidases
  • fibroblast activation protein alpha
  • Gelatinases