Molecular modeling was used to design a rigid analog of sitagliptin 1. The X-ray crystal structure of sitagliptin bound to DPP-4 suggested that the central beta-amino butyl amide moiety could be replaced with a cyclohexylamine group. This was confirmed by structural analysis and the resulting analog 2a was synthesized and found to be a potent DPP-4 inhibitor (IC(50)=21 nM) with excellent in vivo activity and pharmacokinetic profile.
        
Representative scheme of DPP4N_Peptidase_S9 structure and an image from PDBsum server
no Image
Databases
PDB-Sum
2P8S Previously Class, Architecture, Topology and Homologous superfamily - PDB-Sum server
FSSP
2P8SFold classification based on Structure-Structure alignment of Proteins - FSSP server