Identification of a Novel Scaffold for Inhibition of Dipeptidyl Peptidase-4

Mishra, Avinash; Cross, Megan; Hofmann, Andreas; Coster, Mark J.; Karim, Abdul; Sattar, Abdul

doi:10.1089/cmb.2019.0201

Cited by 2 publications

(1 citation statement)

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“…In silico methods are widely used at the early stages of drug design as they provide an opportunity to reduce the number of molecules needed to be screened [ 8 , 17 ]. Some strategies of DPP-4 inhibitor design, like ligand-based and structure-based virtual screening, utilise computer-aided drug discovery methods, allowing to prioritise the space of small molecules, using a series of patterns, calculated in accordance to protein active site structure data and its ligands [ 11 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. Many experiments were carried out on the structural characterisation of synthesised or natural compounds using high-throughput methods.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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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.

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