Design and synthesis of selective DPP9 inhibitors
The aim of this work is to design and synthesize selective inhibitors targeting dipeptidyl peptidase 9 (DPP9), a challenging goal considering the high sequence similarity between DPP9 and other related enzymes, such as DPP4 but especially DPP8. DPP9 has been gaining interest recently as a pivotal role in inflammatory cell death (pyroptosis) could be attributed to DPP9, which lead to the identification of DPP9 as a therapeutic target in acute myeloid leukemia (AML). The thesis primarily concentrates on crafting dipeptide-derived DPP9 inhibitors, inspired by the N-terminal dipeptides of known substrates. By using the marketed DPP4 inhibitor Vildagliptin as a reference, the design strategy involves a bimodular structure incorporating a proline-mimetic as the P1 unit, with or without a nitrile electrophilic warhead, while allowing certain flexibility in the P2 fragment. Vildagliptin's N-(3-hydroxyadamantyl)glycine moiety was thoroughily investigated, by replacing the alcohol group with a variety of functional groups. As a result, several promising compounds have been obtained, exhibiting promising potency and selectivity for DPP9. Notably, compounds 42 and 47 emerged as top candidates, exhibiting low nanomolar DPP9 affinity (3 – 4 nM) alongside significant DPP9-to-DPP8 selectivity indices, in the magnitude of two orders. This comprehensive study not only presents a strategic evolution in designing DPP9-selective inhibitors, but also sheds light on the structural nuances influencing selectivity, providing valuable insights for future drug development and understanding enzyme differentiation in this class.
Antwerp : University of Antwerp, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, Department of Pharmaceutical Sciences , 2024
232 p.
Supervisor: Van der Veken, Pieter [Supervisor]
Supervisor: De Winter, Hans [Supervisor]
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The publisher created published version Available from 13.02.2025
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Creation 15.02.2024
Last edited 16.02.2024
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