Design of potent dipeptidyl peptidase IV (DPP-4) inhibitors by employing a strategy to form a salt bridge with Lys554

doi:10.1016/j.bmcl.2017.05.048

Bioorganic & Medicinal Chemistry Letters

Volume 27, Issue 15, 1 August 2017, Pages 3565-3571

https://doi.org/10.1016/j.bmcl.2017.05.048 Get rights and content

Abstract

We report a design strategy to obtain potent DPP-4 inhibitors by incorporating salt bridge formation with Lys554 in the S1′ pocket. By applying the strategy to the previously identified templates, quinoline 4 and pyridines 16a, 16b, and 17 have been identified as subnanomolar or nanomolar inhibitors of human DPP-4. Docking studies suggested that a hydrophobic interaction with Tyr547 as well as the salt bridge interaction is important for the extremely high potency. The design strategy would be useful to explore a novel design for DPP-4 inhibitors having a distinct structure with a unique binding mode.

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Acknowledgements

The authors would like to thank Nobuo Cho for critical reading of the manuscript and for useful suggestions to improve it. The authors would also like to thank Harumi Hattori and Yusuke Kamada for a statistical analysis of biological data and Koji Takeuchi, Yu Momose, Yuji Ishihara, Shigenori Ohkawa, Takashi Sohda, and Akio Miyake for helpful discussions throughout the study.

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Type 2 Diabetes Mellitus (T2DM) is one of the highly prevalence disorder and increasing day by day worldwidely. T2DM is a metabolic disorder, which is characterized by deficiency in insulin or resistance to insulin and thus increases the glucose levels in the blood. Various approaches are there to treat diabetes but still there is no cure for this disease. DPP-4 inhibitor is a privileged target in the field of drug discovery and provides various opportunities in exploring this target for development of molecules as antidiabetic agents. DPP-4 acts by inhibiting the incretin action and thus decreases the level of blood glucose by imparting minimal side effects. Sitagliptin, vildagliptin, linagliptin etc. are the different DPP-4 based drugs approved throughout the world for the treatment of diabetes mellitus. Cyanopyrrolidines, triazolopiperazine amide, pyrrolidines are basic core nucleus present in various DPP-4 inhibitors and has potential effects. In the past few years, researchers had applied various approaches to synthesize potent DPP-4 inhibitors as antidiabetic agent without side effects like weight gain, cardiovascular risks, retinopathy etc. This review will also emphasize the recent strategies and rationale utilized by researchers for the development of DPP-4 inhibitors. This review also reveals about the various other approaches like molecular modelling, ligand based drug designing, high throughput screening etc. are used by the various research group for the development of potential DPP-4 inhibitors.
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Myriad studies based on β-amino acid skeleton have derived a lot of novel potent DPP-4 inhibitors [69–78]. With the expansion of chemical library, different core structures other than β-amino acid were discovered [47,48,79–87]. These new chemical candidates could generate potent and selective DPP-4 inhibitory activity with binding conformations of type B pattern.
Incretin pathway plays an important role in the development of diabetes medications. Interventions in DPP-4 and GLP-1 receptor have shown remarkable efficacy in experimental and clinical studies and imperatively become one of the most promising therapeutic approaches in the T2DM drug discovery pipeline. Herein, we analyzed the action mechanisms of DPP-4 and GLP-1 receptor targeting the incretin pathway in T2DM treatment. We gave an insight into the structural requirements for the potent DPP-4 inhibitors and revealed a classification of DPP-4 inhibitors by stressing on the binding modes of these ligands to the enzyme. We then reviewed the drug discovery strategies for the development of peptide and non-peptide GLP-1 receptor agonists (GLP-1 RAs). Furthermore, the drug design strategies for DPP-4 inhibitors and GLP-1R agonists were detailed accurately. This review might provide an efficient evidence for the highly potent and selective DPP-4 inhibitors and the GLP-1 RAs, as novel medicines for patients suffering from T2DM.
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2018, European Journal of Medicinal Chemistry
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Compound 46 (232.8 nM) selectively inhibited the activity of DPP-4 over DPP-9 (Fig. 7). New N3-benzylidene (substituted)-2-phenyl-N4-(thiazol-2-yl)-quinazoline-3,4-(4H)-diamine derivatives were designed and synthesized by Ali et al. [67]. Compound 47 (0.76 nM), 48 (1.33 nM), 49 (1.62 nM), 50 (1.22 nM) showed potent DPP-4 inhibitory activity; among them, compound 47 exhibited most promising DPP-4 inhibitory activity and good antioxidant result.
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^a: Present address: Sumika Chemical Analysis Service, Ltd. 17-85, Jusohomachi 2-chome, Yodogawa-ku, Osaka 532-8686, Japan.

^b: Present address: Takeda Pharmaceutical Company Limited, 17-85, Jusohomachi 2-chome, Yodogawa-ku, Osaka 532-8686, Japan.

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Design of potent dipeptidyl peptidase IV (DPP-4) inhibitors by employing a strategy to form a salt bridge with Lys554

Abstract

Graphical abstract

Section snippets

Acknowledgements

Biochem Biophys Res Commun

Bioorg Med Chem

Bioorg Med Chem

Bioorg Med Chem

Bioorg Med Chem

Bioorg Med Chem

Lancet

Ann Med

Curr Diabetes Rev