Heteroannelated pyrrolidines and prolines as inhibitors of dipeptidyl peptidases and related enzymes

Date: 9 July 2015

Venue: UAntwerp, Campus Drie Eiken, Promotiezaal - Universiteitsplein 1 - 2610 Wilrijk

Time: 4:00 PM - 6:00 PM

PhD candidate: Leen Heirbaut

Principal investigator: Koen Augustyns

Co-principal investigator: Pieter Van der Veken

Short description: Public defence Leen Heirbaut - Department Pharmaceutical Sciences


The serine proteases Fibroblast Activation Protein (FAP), dipeptidyl peptidase (DPP) IV, DPP8, DPP9 and prolyl oligopeptidase (PREP) are enzymes belonging to the peptidase Clan SC family. These enzymes are involved in the development and progression of several afflictions, such as carcinogenesis, metastasis, type II diabetes, inflammatory bowel disease and neurodegenerative diseases.

To date, no inhibitors of FAP, DPP8, or DPP9 are available for therapeutic use. Therefore, research into innovative, potent, and selective dipeptide-derived inhibitors of these enzymes is desirable.

The inhibitors of these Clan SC proteases, synthesized during this PhD, consist of a (hetero)annelated pyrrolidine or pyrrolidine-2-carbonitrile building block in P1 position and a fixed set of selected P2 fragments. The pyrrolidine P1 building blocks contain a pyrrolidine ring annelated to a pyrazole, isoxazole, imidazole, or thiazole ring moiety. The pyrrolidine-2-carbonitrile P1 building blocks contain a pyrrolidine-2-carbonitrile ring annelated with a heterocyclic ring or a cyclopropyl ring.

Besides the reversible inhibitors with a carbonitrile warhead, several irreversible diaryl phosphonate inhibitors of DPPIV have been reported in literature. Since little data is available regarding the inhibition of the other DPPs, a series of diphenyl pyrrolidin-2-ylphosphonate inhibitors coupled to a selection of aliphatic, aromatic, or amino acid P2 fragments was synthesized.

The synthetised inhibitors were biochemically evaluated for their inhibitory activity towards FAP, the DPPs, and PREP. The obtained results demonstrate the applicability of the molecules for further optimization and development towards innovative Clan SC inhibitors.