Novel deazaxanthine-based DPP-4 inhibitors have been identified that are potent (IC(50) <10nM) and highly selective versus other dipeptidyl peptidases. Their synthesis and SAR are reported, along with initial efforts to improve the PK profile through decoration of the deazaxanthine core. Optimisation of compound 3a resulted in the identification of compound (S)-4i, which displayed an improved in vitro and ADME profile. Further enhancements to the PK profile were possible by changing from the deazahypoxanthine to the deazaxanthine template, culminating in compound 12g, which displayed good ex vivo DPP-4 inhibition and a superior PK profile in rat, suggestive of once daily dosing in man.
        
Representative scheme of DPP4N_Peptidase_S9 structure and an image from PDBsum server
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Databases
PDB-Sum
4A5S Previously Class, Architecture, Topology and Homologous superfamily - PDB-Sum server
FSSP
4A5SFold classification based on Structure-Structure alignment of Proteins - FSSP server