{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T14:13:50Z","timestamp":1788444830603,"version":"build-2803163510"},"reference-count":21,"publisher":"IMR Press","issue":"8","license":[{"start":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T00:00:00Z","timestamp":1786579200000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Hubei Provincial Department of Education Science and Technology Research Project","award":["No. B2024158"],"award-info":[{"award-number":["No. B2024158"]}]},{"name":"Hubei University of Science and Technology, Scientific Research Projects","award":["2018-19X040"],"award-info":[{"award-number":["2018-19X040"]}]},{"name":"Special Project on Diabetes and Angiopathy","award":["2020TNB11"],"award-info":[{"award-number":["2020TNB11"]}]},{"name":"Special Research Project Funding for Key Pharmacy Disciplines in 2018","award":["2019-20ZY16"],"award-info":[{"award-number":["2019-20ZY16"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmazie"],"abstract":"<jats:p>Background:Diabetes mellitus is a major global health concern. DPP-4 (dipeptidyl peptidase-4) inhibitors containing a 2-cyanopyrrolidine scaffold are in clinical use; however, systematic evaluation of amides derived from amino acids adjacent to the N-2 position of GLP-1 (glucagon-like peptide-1) has not been reported.Methods:A total of eight 2-cyanopyrrolidine derivatives, grouped into three series, were synthesized from N-Boc-protected amino acids via condensation with 2-cyanopyrrolidine followed by deprotection. The compounds were characterized by nuclear magnetic resonance (NMR), elemental analysis, and mass spectrometry (MS). DPP-4 inhibitory activity was evaluated in vitro using a DPP-IV Glo\u2122 assay, with sitagliptin as a control. IC50 (Half Maximal Inhibitory Concentration) values were determined from three independent replicates (n = 3) and calculated by nonlinear regression. Results:Compounds 4d, 4g, and 4h exhibited excellent DPP-4 inhibition, with IC50 values of 1.36 \u00b1 0.09, 5.24 \u00b1 0.31, and 4.83 \u00b1 0.22 nM, respectively. Compound 4d (histidine) was more potent than sitagliptin (6.13 \u00b1 0.42 nM). The bis-cyanopyrrolidine derivatives 4g and 4h also showed strong activity. The remaining compounds (4a\u20134c, 4e, 4f) displayed moderate inhibition (IC50 112\u2013181 nM).Conclusions:Aminoacyl-2-cyanopyrrolidine derivatives bearing an imidazole or bis-cyanopyrrolidine structure are potent DPP-4 inhibitors. These findings highlight the importance of neighboring GLP-1 amino acid residues (positions 1 and 3) in inhibitor design. Further cellular and in vivo studies are warranted to evaluate the therapeutic potential of these compounds.<\/jats:p>","DOI":"10.31083\/pharmazie53112","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T13:26:12Z","timestamp":1788441972000},"source":"Crossref","is-referenced-by-count":0,"title":["Synthesis of Aminoacyl-2-Cyanopyrrolidine Compounds and Their Inhibitory Effect on the DPP-4 Enzyme"],"prefix":"10.31083","volume":"81","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-1424-7506","authenticated-orcid":true,"given":"Liyuan","family":"Guo","sequence":"first","affiliation":[{"name":"School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, 437100 Xianning, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-9335-8955","authenticated-orcid":true,"given":"Man","family":"Di","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, 437100 Xianning, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-6642-120X","authenticated-orcid":true,"given":"Zhiyan","family":"Dong","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, 437100 Xianning, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-4306-7547","authenticated-orcid":true,"given":"Da","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, 437100 Xianning, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-9040-8136","authenticated-orcid":true,"given":"Xiaoqing","family":"Zhu","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, 437100 Xianning, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6697-1753","authenticated-orcid":true,"given":"Shi","family":"Wu","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, 437100 Xianning, Hubei, China"},{"name":"Hubei Key Laboratory of Diabetes and Angiopathy, Hubei University of Science and Technology, 437100 Xianning, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-8789-5173","authenticated-orcid":true,"given":"Chao","family":"Liu","sequence":"additional","affiliation":[{"name":"Hubei Key Laboratory of Diabetes and Angiopathy, Hubei University of Science and Technology, 437100 Xianning, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2026,8,13]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Rooney MR, He JH, Salpea P, Genitsaridi I, Magliano DJ, Boyko EJ, et al. 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