Potent and selective inhibitors of fibroblast activation protein (FAP).

摘要

Fibroblast activation protein (FAP) is a serine protease that has been convincingly linked to tumor growth and other 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. Furthermore, FAP expression is a possible prognostic marker in several epithelial cancers.;At the onset of the study, no FAP inhibitors with high selectivity against both the closely related dipeptidyl peptidases (DPP's) and prolyl oligopeptidase (PREP) were reported. The present study describes the discovery of a new class of FAP inhibitors with the N-4-quinolinoyl-Gly-(2 S)-cyanoPro scaffold.;The most promising inhibitors combine low nanomolar FAP inhibition and high selectivity indices (>103) with respect to both the DPP's and PREP. A linker was developed to easily link these inhibitors with chromophores and nanoparticles with click chemistry.;The log D values, plasma stabilities, and microsomal stabilities of selected compounds were found to be highly satisfactory. Pharmacokinetic evaluation of selected inhibitors in rats demonstrated high oral bioavailability, plasma half-life and the potential to selectively and complete in vivo FAP inhibition. Collaborations for the in vivo evaluation of selected inhibitors have been initiated.;In another part of this work, the FDA-approved xanthine-based DPP-IV inhibitor linagliptin was used as a starting point for a SAR study that aimed to identify structural determinants that selectively increase FAP-affinity of linagliptin analogues. By investigating the influence of the substitution pattern on N1, N7 and C8 of the xanthine scaffold, we managed to decouple DPPIV and FAP potency and identified the first selective xanthine-based FAP inhibitors with low micromolar potency.