title: Selective Inhibitors of Fibroblast Activation Protein (FAP) with a (4-Quinolinoyl)-glycyl-2-cyanopyrrolidine Scaffold.
abstract: Fibroblast activation protein (FAP) is a serine protease that is generally accepted to play an important role in tumor growth and other diseases involving tissue remodeling. Currently there are no FAP inhibitors with reported selectivity toward both the closely related dipeptidyl peptidases (DPPs) and prolyl oligopeptidase (PREP). We present the discovery of a new class of FAP inhibitors with a N-(4-quinolinoyl)-Gly-(2-cyanopyrrolidine) scaffold. We have explored the effects of substituting the quinoline ring and varying the position of its sp(2) hybridized nitrogen atom. The most promising inhibitors combined low nanomolar FAP inhibition and high selectivity indices (>10(3)) with respect to both the DPPs and PREP. Preliminary experiments on a representative inhibitor demonstrate that plasma stability, kinetic solubility, and log D of this class of compounds can be expected to be satisfactory.
authors.affiliation: Medicinal Chemistry (UAMC), Department of Pharmaceutical Sciences, University of Antwerp (UA) , Universiteitsplein 1, B-2610 Antwerp, Belgium.
authors.forename: Koen
authors.initials: K
authors.lastname: Jansen
authors.affiliation: Medicinal Chemistry (UAMC), Department of Pharmaceutical Sciences, University of Antwerp (UA) , Universiteitsplein 1, B-2610 Antwerp, Belgium.
authors.forename: Leen
authors.initials: L
authors.lastname: Heirbaut
authors.affiliation: Fox Chase Cancer Center , 333 Cottman Avenue, Philadelphia, Pennsylvania 19111-2497, United States.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Cheng
authors.affiliation: Medicinal Chemistry (UAMC), Department of Pharmaceutical Sciences, University of Antwerp (UA) , Universiteitsplein 1, B-2610 Antwerp, Belgium.
authors.forename: Jurgen
authors.initials: J
authors.lastname: Joossens
authors.affiliation: Medicinal Chemistry (UAMC), Department of Pharmaceutical Sciences, University of Antwerp (UA) , Universiteitsplein 1, B-2610 Antwerp, Belgium.
authors.forename: Oxana
authors.initials: O
authors.lastname: Ryabtsova
authors.affiliation: Laboratory of Microbiology, Parasitology and Hygiene (LMPH), Departments of Pharmaceutical and Biomedical Sciences, University of Antwerp (UA) , Universiteitsplein 1, B-2610 Antwerp, Belgium.
authors.forename: Paul
authors.initials: P
authors.lastname: Cos
authors.affiliation: Laboratory of Microbiology, Parasitology and Hygiene (LMPH), Departments of Pharmaceutical and Biomedical Sciences, University of Antwerp (UA) , Universiteitsplein 1, B-2610 Antwerp, Belgium.
authors.forename: Louis
authors.initials: L
authors.lastname: Maes
authors.affiliation: Medical Biochemistry, Department of Pharmaceutical Sciences, University of Antwerp (UA) , Universiteitsplein 1, B-2610 Antwerp, Belgium.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Lambeir
authors.affiliation: Medical Biochemistry, Department of Pharmaceutical Sciences, University of Antwerp (UA) , Universiteitsplein 1, B-2610 Antwerp, Belgium.
authors.forename: Ingrid
authors.initials: I
authors.lastname: De Meester
authors.affiliation: Medicinal Chemistry (UAMC), Department of Pharmaceutical Sciences, University of Antwerp (UA) , Universiteitsplein 1, B-2610 Antwerp, Belgium.
authors.forename: Koen
authors.initials: K
authors.lastname: Augustyns
authors.affiliation: Medicinal Chemistry (UAMC), Department of Pharmaceutical Sciences, University of Antwerp (UA) , Universiteitsplein 1, B-2610 Antwerp, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Van der Veken
keywords: Fibroblast activation protein (FAP); dipeptidyl peptidase IV (DPPIV); prolyl oligopeptidase (PREP); seprase