2. Academic Validation
  3. Selective Inhibitors of Fibroblast Activation Protein (FAP) with a (4-Quinolinoyl)-glycyl-2-cyanopyrrolidine Scaffold

Selective Inhibitors of Fibroblast Activation Protein (FAP) with a (4-Quinolinoyl)-glycyl-2-cyanopyrrolidine Scaffold

  • ACS Med Chem Lett. 2013 Mar 18;4(5):491-6. doi: 10.1021/ml300410d.
Koen Jansen 1,  Leen Heirbaut 1,  Jonathan D Cheng 2,  Jurgen Joossens 1,  Oxana Ryabtsova 1,  Paul Cos 3,  Louis Maes 3,  Anne-Marie Lambeir 4,  Ingrid De Meester 4,  Koen Augustyns 1,  Pieter Van der Veken 1
Affiliations

Affiliations

  • 1 Medicinal Chemistry (UAMC), Department of Pharmaceutical Sciences, University of Antwerp (UA) , Universiteitsplein 1, B-2610 Antwerp, Belgium.
  • 2 Fox Chase Cancer Center , 333 Cottman Avenue, Philadelphia, Pennsylvania 19111-2497, United States.
  • 3 Laboratory of Microbiology, Parasitology and Hygiene (LMPH), Departments of Pharmaceutical and Biomedical Sciences, University of Antwerp (UA) , Universiteitsplein 1, B-2610 Antwerp, Belgium.
  • 4 Medical Biochemistry, Department of Pharmaceutical Sciences, University of Antwerp (UA) , Universiteitsplein 1, B-2610 Antwerp, Belgium.
PMID: 24900696 DOI: 10.1021/ml300410d
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.

Keywords

Fibroblast activation protein (FAP); dipeptidyl peptidase IV (DPPIV); prolyl oligopeptidase (PREP); seprase.

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