Probing for improved selectivity with dipeptide-derived inhibitors of dipeptidyl peptidases 8 and 9: the impact of P1-variation

Leen Heirbaut; Sebastiaan van Goethem; Koen Jansen; Hans de Winter; Nicole Lamoen; Jurgen Joossens; Jonathan Cheng; Xin Chen; Anne-Marie Lambeir; Ingrid de Meester; Koen Augustyns; Pieter van der Veken

doi:10.1039/C5MD00454C

Probing for improved selectivity with dipeptide-derived inhibitors of dipeptidyl peptidases 8 and 9: the impact of P1-variation†

Leen Heirbaut,‡^a Sebastiaan van Goethem,‡^a Koen Jansen,^a Hans de Winter,^a Nicole Lamoen,^b Jurgen Joossens,^a Jonathan Cheng,^c Xin Chen,^d Anne-Marie Lambeir,^b Ingrid de Meester,^b Koen Augustyns

^a and Pieter van der Veken*^a

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* Corresponding authors

^a Medicinal Chemistry/UAMC, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk-Antwerp, Belgium
E-mail: pieter.vanderveken@uantwerpen.be

^b Laboratory of Medical Biochemistry, University of Antwerp, Universiteitsplein 1, B-2610 Wirijk-Antwerp, Belgium

^c Fox-Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA-19111-2497, USA

^d National Health Research Institutes, 35 Keynan Road, Zhunan, Miaoli County 350, Taiwan

Abstract

Selected pyrrolidines, 2-cyanopyrrolidines and heteroaromatic isoindoline analogues were evaluated as P1-residues in dipeptide-derived inhibitors of DPP8/9. Potency testing indicates that DPP8 or DPP9 specificity cannot be obtained with the selected set of P1- and P2-fragments. Nonetheless, the nanomolar DPP8/9 potencies and remarkable selectivities with respect to DPP IV and DPPII, makes inhibitors 4c and 4h suitable “leads” for future inhibitor optimization effort.

MedChemComm

Probing for improved selectivity with dipeptide-derived inhibitors of dipeptidyl peptidases 8 and 9: the impact of P1-variation†

Abstract

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Probing for improved selectivity with dipeptide-derived inhibitors of dipeptidyl peptidases 8 and 9: the impact of P1-variation

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