{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T15:56:18Z","timestamp":1768924578003,"version":"3.49.0"},"reference-count":26,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T00:00:00Z","timestamp":1745798400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Russian Federation, CITSEP (Centre of Information Technologies and Systems of Executive Power)","award":["121031600199-9"],"award-info":[{"award-number":["121031600199-9"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: 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. Methods: This study combines chemical synthesis, molecular modelling, and inhibitory activity assays to characterise the structure\u2013activity relationship of novel isomeric 1,2,4-oxadiazole-substituted derivatives of the 2-azabicyclo[2.2.1]heptane scaffold acylated with (R)-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid. Results: 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 9a (IC50 = 4.3 nM), which did not mediate any substantial inhibition of DPP-8 and DPP-9. Conclusions: This study demonstrates that pseudo peptides incorporating (R)-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 9a, a strong candidate for further development in T2DM treatment.<\/jats:p>","DOI":"10.3390\/ph18050642","type":"journal-article","created":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T11:35:13Z","timestamp":1746185713000},"page":"642","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["3-(3-Azabicyclo[2, 2, 1]heptan-2-yl)-1,2,4-oxadiazoles as Novel Potent DPP-4 Inhibitors to Treat T2DM"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8391-8823","authenticated-orcid":false,"given":"Tatiana V.","family":"Zinevich","sequence":"first","affiliation":[{"name":"Department of Bioorganic Chemistry, Faculty of Biology, Lomonosov Moscow State University, 119991 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2322-3819","authenticated-orcid":false,"given":"Ivan O.","family":"Maslov","sequence":"additional","affiliation":[{"name":"Department of Bioorganic Chemistry, Faculty of Biology, Lomonosov Moscow State University, 119991 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olga G.","family":"Kirichenko","sequence":"additional","affiliation":[{"name":"LLC Institute of Mitoengineering MSU, 119899 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sergey V.","family":"Shorshnev","sequence":"additional","affiliation":[{"name":"MIREA, Russian Technological University, Campus in Malaya Pirogovskaya Street, 119435 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0385-922X","authenticated-orcid":false,"given":"Maxim A.","family":"Gureev","sequence":"additional","affiliation":[{"name":"Laboratory of Bio- and Chemoinformatics, HSE University, 16 Soyuza Pechatnikov, 190121 Saint-Petersburg, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fedor M.","family":"Dolgushin","sequence":"additional","affiliation":[{"name":"Kurnakov Institute of General and Inorganic Chemistry RAS, 119071 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5450-3135","authenticated-orcid":false,"given":"Yuri B.","family":"Porozov","sequence":"additional","affiliation":[{"name":"Laboratory of Bio- and Chemoinformatics, HSE University, 16 Soyuza Pechatnikov, 190121 Saint-Petersburg, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4726-333X","authenticated-orcid":false,"given":"Vladimir M.","family":"Trukhan","sequence":"additional","affiliation":[{"name":"Institute for Translational Medicine and Biotechnology, I. M. Sechenov First Moscow State Medical University, 119991 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1038\/nature05482","article-title":"Mechanisms linking obesity to insulin resistance and type 2 diabetes","volume":"444","author":"Kahn","year":"2006","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1751","DOI":"10.2337\/dc14-0396","article-title":"\u03b2-Cell failure in type 2 diabetes: Postulated mechanisms and prospects for prevention and treatment","volume":"37","author":"Halban","year":"2014","journal-title":"Diabetes Care"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"(2020). Classification and diagnosis of diabetes: Standards of Medical Care in Diabetes\u20142020. 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