{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T13:48:08Z","timestamp":1785332888831,"version":"3.55.0"},"reference-count":43,"publisher":"Wiley","issue":"23","license":[{"start":{"date-parts":[[2014,9,5]],"date-time":"2014-09-05T00:00:00Z","timestamp":1409875200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001809","name":"the National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["81172932 and 81273376"],"award-info":[{"award-number":["81172932 and 81273376"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"the Natural Science Foundation of Jiangsu Province","award":["BK2012356"],"award-info":[{"award-number":["BK2012356"]}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2014,12]]},"abstract":"<jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>The short biological half\u2010life limits the therapeutic use of glucagon\u2010like peptide\u20101 (<jats:styled-content style=\"fixed-case\">GLP<\/jats:styled-content>\u20101) and chemical modification to improve the interaction of peptides with serum albumin represents an effective strategy to develop long\u2010acting peptide analogues. Coumarin, a natural product, is known to bind tightly to plasma proteins and possesses many biological activities. Therefore, we designed and synthesized a series of coumarin\u2010modified <jats:styled-content style=\"fixed-case\">GLP<\/jats:styled-content>\u20101 derivatives, hypothesizing that conjugation with coumarin would retain the therapeutic effects and prolong the biological half\u2010life of the conjugates.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Four cysteine\u2010modified <jats:styled-content style=\"fixed-case\">GLP<\/jats:styled-content>\u20101 analogues (1\u20134) were prepared using <jats:styled-content style=\"fixed-case\">G<\/jats:styled-content>ly<jats:sub>8<\/jats:sub>\u2010<jats:styled-content style=\"fixed-case\">GLP<\/jats:styled-content>\u20101(7\u201336)\u2010<jats:styled-content style=\"fixed-case\"><jats:roman>NH<jats:sub>2<\/jats:sub><\/jats:roman><\/jats:styled-content> peptide as a starting point. These analogues were conjugated with two coumarin maleimides to yield eight compounds (conjugates 6\u201313) for testing. Activation of human GLP\u20101 receptors, stability to enzymic inactivation in plasma and binding to human albumin were assessed <jats:italic>in vitro<\/jats:italic>. <jats:italic>In vivo<\/jats:italic>, effects on oral glucose tolerance tests (OGTT) in rats and on blood glucose levels in <jats:italic>db\/db<\/jats:italic> mice were studied.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Most conjugates showed well preserved receptor activation efficacy, enhanced albumin\u2010binding properties and improved <jats:italic>in vitro<\/jats:italic> plasma stability and conjugate 7 was selected to undergo further assessment. In rats, conjugate 7 had a longer circulating t<jats:sub>1\/2<\/jats:sub> than exendin\u20104 or liraglutide. A prolonged antidiabetic effect of conjugate 7 was observed after OGTT in rats and a prolonged hypoglycaemic effect in <jats:italic>db\/db<\/jats:italic> mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>Cysteine\u2010specific coumarin conjugation with <jats:styled-content style=\"fixed-case\">GLP<\/jats:styled-content>\u20101 offers a useful approach to the development of long\u2010acting incretin\u2010based antidiabetic agents. Conjugate 7 is a promising long\u2010lasting <jats:styled-content style=\"fixed-case\">GLP<\/jats:styled-content>\u20101 derivative deserving further investigation.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.12843","type":"journal-article","created":{"date-parts":[[2014,7,15]],"date-time":"2014-07-15T19:21:35Z","timestamp":1405452095000},"page":"5252-5264","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":49,"title":["Novel coumarin modified <scp>GLP<\/scp>\u20101 derivatives with enhanced plasma stability and prolonged <i>in vivo<\/i> glucose\u2010lowering ability"],"prefix":"10.1111","volume":"171","author":[{"given":"Jing","family":"Han","sequence":"first","affiliation":[{"name":"Center of Drug Discovery State Key Laboratory of Natural Medicines China Pharmaceutical University  Nanjing 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