Modifications of DPP-4 inhibitor 5, that was discovered by structure based design, are described and structure-activity relationships discussed. With analogue 7k one of the most potent non-covalent inhibitors of DPP-4 reported to date (IC(50)=0.38nM) was discovered. X-ray structure of inhibitor 7k bound to DPP-4 revealed a hydrogen bonding interaction with Q553. First successful efforts in balancing overall properties, as demonstrated by improved metabolic stability, highlight the potential of this series.
        
Representative scheme of DPP4N_Peptidase_S9 structure and an image from PDBsum server
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Databases
PDB-Sum
3H0C Previously Class, Architecture, Topology and Homologous superfamily - PDB-Sum server
FSSP
3H0CFold classification based on Structure-Structure alignment of Proteins - FSSP server