Design, Synthesis and Biological Evaluation of Neogliptin, a Novel 2-Azabicyclo[2.2.1]heptane-Based Inhibitor of Dipeptidyl Peptidase-4 (DPP-4)

• Published in: Pharmaceuticals (Basel, Switzerland) Switzerland), 2022-02, Vol.15 (3), p.273
• Main Authors: Maslov, Ivan O, Zinevich, Tatiana V, Kirichenko, Olga G, Trukhan, Mikhail V, Shorshnev, Sergey V, Tuaeva, Natalya O, Gureev, Maxim A, Dahlén, Amelia D, Porozov, Yuri B, Schiöth, Helgi B, Trukhan, Vladimir M
• Format: Article
• Language: English
• Subjects: Amino acids; Binding sites; Cardiotoxicity; Clinical trials; DPP-4 inhibitors; FDA approval; Glucagon; Hyperglycemia; Ligands; molecular docking; Peptides; Proteins; rotameric forms; Signal transduction; stereoisomerism; structure-activity relationship; type 2 diabetes mellitus
• ISSN: 1424-8247; 1424-8247
• DOI: 10.3390/ph15030273

Compounds that contain (R)-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid substituted with bicyclic amino moiety (2-aza-bicyclo[2.2.1]heptane) were designed using molecular modelling methods, synthesised, and found to be potent DPP-4 (dipeptidyl peptidase-4) inhibitors. Compound (IC50 = 16.8 ± 2.2 nM), named neogliptin, is a more potent DPP-4 inhibitor than vildagliptin and sitagliptin. Neogliptin interacts with key DPP-4 residues in the active site and has pharmacophore parameters similar to vildagliptin and sitagliptin. It was found to have a low cardiotoxic effect compared to sitagliptin, and it is superior to vildagliptin in terms of ADME properties. Moreover, compound is stable in aqueous solutions due to its low intramolecular cyclisation potential. These findings suggest that compound has unique properties and can act as a template for further type 2 diabetes mellitus drug development.