A series of beta-aminoacyl containing thiazolidine derivatives was synthesized and evaluated for their ability to inhibit DPP-IV. Several thiazolidine derivatives with an acid moiety were found to be potent DPP-IV inhibitors. Among them, compound 2da is the most active in this series with an IC(50) value of 1 nM, and it showed excellent selectivity over DPP-IV related enzymes including DPP-2, DPP-8, and DPP-9. Compound 2da is chemically and metabolically stable, and showed no CYP inhibition, hERG binding or cytotoxicity. Compound 2db, an ester prodrug of 2da, showed good in vivo DPP-IV inhibition after oral administration in rat and dog models.
        
Representative scheme of DPP4N_Peptidase_S9 structure and an image from PDBsum server
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3Q8W Previously Class, Architecture, Topology and Homologous superfamily - PDB-Sum server
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3Q8WFold classification based on Structure-Structure alignment of Proteins - FSSP server