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

Ivan O Maslov,Tatiana V Zinevich,Natalya O Tuaeva,Yuri B Porozov,Mikhail V Trukhan,Maxim A Gureev,Vladimir M Trukhan,Olga G Kirichenko,Sergey V Shorshnev,Amelia D Dahlén,Helgi B Schiöth

doi:10.3390/ph15030273

Abstract

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 12a (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 12a is stable in aqueous solutions due to its low intramolecular cyclisation potential. These findings suggest that compound 12a has unique properties and can act as a template for further type 2 diabetes mellitus drug development.

Highlights

Pharmacological therapy for type 2 diabetes mellitus (T2DM) patients has developed considerably over the past decades involving several new strategies [1,2,3]
This intramolecular cyclisation leads to the formation of substituted diketopiperazines with no affinity to Dipeptidyl peptidase (DPP)-4 (Figure 1)
We show that pseudo peptides containing trifluoro-substituted aromatic βamino acid and the proline functional analogue inhibit DPP-4

Summary

Introduction

Pharmacological therapy for type 2 diabetes mellitus (T2DM) patients has developed considerably over the past decades involving several new strategies [1,2,3] Many of these strategies involve more patient-friendly ways of drug administration. One of the most recent and promising methods to treat T2DM is to use dipeptidyl peptidase 4 (DPP-4) inhibitors, which are called gliptins [4,5,6,7,8,9] They prevent the degradation of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), stimulate insulin synthesis, suppress glucagon secretion, inhibit appetite, reduce body weight, slow gastric emptying, and can 4.0/).

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Conclusion