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.

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

Figures

Figure 1

Structure of reference inhibitors used in this study: Val-boroPro (1) and linagliptin (2).

Scheme 1. Synthesis of Target Compounds 3-39

Reagents and conditions: (a) Boc-glycine, HATU, DIPEA, DMF-DCM, rt, 71%; (b) trifluoroacetic anhydride, pyridine, THF, 0 °C, 92%; (c) (i) TFA, MeCN, 0 °C, 24h; (ii) HCl, diethylether, 84%; (d) HATU, DIPEA, R-COOH or 1-chloro-N,N,2-trimethylprop-1-en-1-amine, RCOOH, TEA or RCOCl, TEA, 20–76%.