3-(3-Azabicyclo[2, 2, 1]heptan-2-yl)-1,2,4-oxadiazoles as Novel Potent DPP-4 Inhibitors to Treat T2DM

3-(3-Azabicyclo[2, 2, 1]heptan-2-yl)-1,2,4-oxadiazoles as Novel Potent DPP-4 Inhibitors to Treat T2DM

<b>Background</b>: Type 2 diabetes mellitus (T2DM) is a prevalent metabolic disease with global implications, necessitating effective management strategies. Dipeptidyl peptidase IV (DPP-4) inhibitors have shown promise as potent agents for T2DM treatment. <b>Methods</b>: This...

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Main Authors: Tatiana V. Zinevich, Ivan O. Maslov, Olga G. Kirichenko, Sergey V. Shorshnev, Maxim A. Gureev, Fedor M. Dolgushin, Yuri B. Porozov, Vladimir M. Trukhan
Format: Article
Language:English
Published: MDPI AG 2025-04-01
Series:Pharmaceuticals
Subjects:
type 2 diabetes mellitus
DPP-4 inhibitors
molecular docking
structure–activity relationship
stereoisomerism
oxadiazoles
Online Access:https://www.mdpi.com/1424-8247/18/5/642
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Summary:<b>Background</b>: Type 2 diabetes mellitus (T2DM) is a prevalent metabolic disease with global implications, necessitating effective management strategies. Dipeptidyl peptidase IV (DPP-4) inhibitors have shown promise as potent agents for T2DM treatment. <b>Methods</b>: This study combines chemical synthesis, molecular modelling, and inhibitory activity assays to characterise the structure–activity relationship of novel isomeric 1,2,4-oxadiazole-substituted derivatives of the 2-azabicyclo[2.2.1]heptane scaffold acylated with (<i>R</i>)-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid. <b>Results</b>: In this article, we demonstrate the efficacy of new compounds as robust inhibitors of DPP-4. The attempts to further modify neogliptin (our lead compound described previously) resulted in a more potent DPP-4 inhibitor <b>9a</b> (IC<sub>50</sub> = 4.3 nM), which did not mediate any substantial inhibition of DPP-8 and DPP-9. <b>Conclusions</b>: This study demonstrates that pseudo peptides incorporating (<i>R</i>)-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid, a 2-aza-bicyclo[2.2.1]heptane moiety, and 1,2,4-oxadiazole substituents act as potent and selective DPP-4 inhibitors. By the stereochemical refinement of oxadiazole derivatives of neogliptin, we discovered compound <b>9a</b>, a strong candidate for further development in T2DM treatment.
ISSN:1424-8247

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