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Design, synthesis and anti-diabetic activity of triazolotriazine derivatives as dipeptidyl peptidase-4 (DPP-4) inhibitors.

Abstract：

:Type 2 diabetes mellitus (T2DM) is one of the major global metabolic disorders characterized by insulin resistance and chronic hyperglycemia. Inhibition of the enzyme, dipeptidyl peptidase-4 (DPP-4) has been proved as successful and safe therapy for the treatment of T2DM since last decade. In order to design novel DPP-4 inhibitors, various in silico studies such as 3D-QSAR, pharmacophore modeling and virtual screening were performed and on the basis of the combined results of them, total 50 triazolo[5,1-c][1,2,4]triazine derivatives were designed and mapped on the best pharmacophore model. From this, best 25 derivatives were docked onto the active site of DPP-4 enzyme and in silico ADMET properties were also predicted. Finally, top 17 derivatives were synthesized and characterized using FT-IR, Mass, 1H NMR and 13C NMR spectroscopy. Purity of compounds was checked using HPLC. These derivatives were then evaluated for in vitro DPP-4 inhibition. The most promising compound 15q showed 28.05μM DPP-4 IC50 with 8-10-fold selectivity over DPP-8 and DPP-9 so selected for further in vivo anti-diabetic evaluation. During OGTT in normal C57BL/6J mice, compound 15q reduced blood glucose excursion in a dose-dependent manner. Chronic treatment for 28days with compound 15q improved the serum glucose levels in type 2 diabetic Sprague Dawley rats wherein diabetes was induced by high fat diet and low dose streptozotocin. This suggested that compound 15q is a moderately potent and selective hit molecule which can be further optimized structurally to increase the efficacy and overall pharmacological profile as DPP-4 inhibitor.

journal_name

Bioorg Chem

journal_title

Bioorganic chemistry

authors

Patel BD,Bhadada SV,Ghate MD

doi

10.1016/j.bioorg.2017.03.004

subject

Has Abstract

pub_date

2017-06-01 00:00:00

pages

345-358

eissn

0045-2068

issn

1090-2120

pii

S0045-2068(16)30403-5

journal_volume

72

pub_type

杂志文章

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