A series of 4-substituted proline amides was synthesized and evaluated as inhibitors of dipeptidyl pepdidase IV for the treatment of type 2 diabetes. (3,3-Difluoro-pyrrolidin-1-yl)-[(2S,4S)-(4-(4-pyrimidin-2-yl-piperazin-1-yl)-pyrr olidin-2-yl]-methanone (5) emerged as a potent (IC(50) = 13 nM) and selective compound, with high oral bioavailability in preclinical species and low plasma protein binding. Compound 5, PF-00734200, was selected for development as a potential new treatment for type 2 diabetes.
        
Representative scheme of DPP4N_Peptidase_S9 structure and an image from PDBsum server
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Databases
PDB-Sum
3F8S Previously Class, Architecture, Topology and Homologous superfamily - PDB-Sum server
FSSP
3F8SFold classification based on Structure-Structure alignment of Proteins - FSSP server