Vildagliptin‐Derived Dipeptidyl Peptidase 9 (DPP9) Inhibitors: Identification of a DPP8/9‐Specific Lead

Vildagliptin is a marketed DPP4 inhibitor, used in the management of type 2 diabetes. The molecule also has notable DPP8/9 affinity, with some preference for DPP9. Therefore, we aimed to use vildagliptin as a starting point for selective DPP8/9 inhibitors, and to engineer out the parent compound...

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Published in:ChemMedChem 2022-08, Vol.17 (15), p.e202200097-n/a
Main Authors: Benramdane, Siham, De Loose, Joni, Beyens, Olivier, Van Rymenant, Yentl, Vliegen, Gwendolyn, Augustyns, Koen, De Winter, Hans, De Meester, Ingrid, Van der Veken, Pieter
Format: Article
Language:English
Subjects:
Affinity
Diabetes mellitus (non-insulin dependent)
DPP8/9
Glycine
Inhibitors
Molecular dynamics
Optimization
Peptidase
Peptidases
Selectivity
selectivity profiling
structure-activity profiling
vildagliptin
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Summary:Vildagliptin is a marketed DPP4 inhibitor, used in the management of type 2 diabetes. The molecule also has notable DPP8/9 affinity, with some preference for DPP9. Therefore, we aimed to use vildagliptin as a starting point for selective DPP8/9 inhibitors, and to engineer out the parent compound's DPP4‐affinity. In addition, we wanted to identify substructures in the obtained molecules that allow their further optimization into inhibitors with maximal DPP9 selectivity. Various 2S‐cyanopyrrolidines and isoindoline were investigated as P1 residues of vildagliptin analogs. The obtained set was expanded with derivatives bearing O‐substituted, N‐(3‐hydroxyadamantyl)glycine moieties at the P2 position. In this way, representatives were discovered with DPP8/9 potencies comparable to the parent molecule, but with overall selectivity towards DPP4, DPP2, FAP, and PREP. Furthermore, the most promising molecules in this series have a 4‐ to 7‐fold preference for DPP9 over DPP8. Finally, a molecular dynamics study was carried out to maximize our insight into experimental selectivity data. Switching out selectivity: Vildagliptin is a marketed dipeptidyl peptidase 4 (DPP4) inhibitor, used in the management of type 2 diabetes. It has notable DPP8/9 affinity, with some preference for DPP9. We made structural modifications to vildagliptin in our pursuit of selective DPP8/9 inhibitors that lack the parent compound's affinity for DPP4. A molecular dynamics study accompanies our SAR results for a clearer understanding of this selectivity profile.
ISSN:1860-7179
1860-7187
DOI:10.1002/cmdc.202200097