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新型基于2-氮杂双环[2.2.1]庚烷的二肽基肽酶-4（DPP-4）抑制剂奈格列净的设计、合成及生物学评价

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

作者信息

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

机构信息

Department of Bioorganic chemistry, Faculty of Biology, Lomonosov Moscow State University, 119991 Moscow, Russia.

LLC Institute of Mitoengineering MSU, 119899 Moscow, Russia.

出版信息

Pharmaceuticals (Basel). 2022 Feb 22;15(3):273. doi: 10.3390/ph15030273.

DOI:10.3390/ph15030273
PMID:35337071
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8949241/
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 (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 is stable in aqueous solutions due to its low intramolecular cyclisation potential. These findings suggest that compound has unique properties and can act as a template for further type 2 diabetes mellitus drug development.

摘要

利用分子建模方法设计、合成了含有被双环氨基部分（2-氮杂双环[2.2.1]庚烷）取代的(R)-3-氨基-4-(2,4,5-三氟苯基)丁酸的化合物，发现这些化合物是有效的二肽基肽酶-4（DPP-4）抑制剂。化合物（IC50 = 16.8 ± 2.2 nM），名为奈格列净，是一种比维格列汀和西格列汀更有效的DPP-4抑制剂。奈格列净与活性位点中的关键DPP-4残基相互作用，并且具有与维格列汀和西格列汀相似的药效团参数。与西格列汀相比，发现其具有低心脏毒性作用，并且在药物代谢动力学性质方面优于维格列汀。此外，化合物由于其低分子内环化潜力而在水溶液中稳定。这些发现表明化合物具有独特的性质，并且可以作为进一步开发2型糖尿病药物的模板。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1924/8949241/87a1085c0932/pharmaceuticals-15-00273-g011.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1924/8949241/9823dd7e3497/pharmaceuticals-15-00273-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1924/8949241/7d56084a4c02/pharmaceuticals-15-00273-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1924/8949241/6ce6f84572d8/pharmaceuticals-15-00273-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1924/8949241/2b74b019311e/pharmaceuticals-15-00273-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1924/8949241/cb784c7fcde4/pharmaceuticals-15-00273-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1924/8949241/87a1085c0932/pharmaceuticals-15-00273-g011.jpg

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