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

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• 作者：Koen Jansen ; Leen Heirbaut ; Jonathan D. Cheng ; Jurgen Joossens ; Oxana Ryabtsova ; Paul Cos ; Louis Maes ; Anne-Marie Lambeir ; Ingrid De Meester ; Koen Augustyns ; Pieter Van der Veken
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2013
• 出版时间：May 9, 2013
• 年：2013
• 卷：4
• 期：5
• 页码：491-496
• 全文大小：355K
• 年卷期：v.4,no.5(May 9, 2013)
• ISSN：1948-5875

文摘

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 sp² hybridized nitrogen atom. The most promising inhibitors combined low nanomolar FAP inhibition and high selectivity indices (>10³) 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