Статья

Extended Structure–Activity Relationship and Pharmacokinetic Investigation of (4-Quinolinoyl)glycyl-2-cyanopyrrolidine Inhibitors of Fibroblast Activation Protein (FAP)

Koen JansenMedicinal Chemistry, Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, BelgiumLeen HeirbautMedicinal Chemistry, Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, BelgiumRobert VerkerkMedical Biochemistry, Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, BelgiumJonathan D. ChengFox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, Pennsylvania 19111-2497, United StatesJurgen JoossensMedicinal Chemistry, Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, BelgiumPaul CosLaboratory of Microbiology, Parasitology, and Hygiene, Departments of Pharmaceutical Sciences and Biomedical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, BelgiumLouis MaesLaboratory of Microbiology, Parasitology, and Hygiene, Departments of Pharmaceutical Sciences and Biomedical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, BelgiumAnne‐Marie LambeirMedical Biochemistry, Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, BelgiumIngrid De MeesterMedical Biochemistry, Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, BelgiumKoen AugustynsMedicinal Chemistry, Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, BelgiumPieter Van der VekenMedicinal Chemistry, Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium

2014en

ABI

Аннотация

Fibroblast activation protein (FAP) is a serine protease related to dipeptidyl peptidase IV (DPPIV). It has been convincingly linked to multiple 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. We previously discovered the N-4-quinolinoyl-Gly-(2S)-cyanoPro scaffold as a possible entry to highly potent and selective FAP inhibitors. In the present study, we explore in detail the structure-activity relationship around this core scaffold. We report extensively optimized compounds that display low nanomolar inhibitory potency and high selectivity against the related dipeptidyl peptidases (DPPs) DPPIV, DPP9, DPPII, and prolyl oligopeptidase (PREP). The log D values, plasma stabilities, and microsomal stabilities of selected compounds were found to be highly satisfactory. Pharmacokinetic evaluation in mice of selected inhibitors demonstrated high oral bioavailability, plasma half-life, and the potential to selectively and completely inhibit FAP in vivo.

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Идентификаторы

DOI: 10.1021/jm500031w

Цитирования и источники

Цитирований: 2Использованных источников: 0

Показатели — AkademScholar