{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,7]],"date-time":"2025-11-07T19:05:31Z","timestamp":1762542331622},"reference-count":22,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2014,12,17]],"date-time":"2014-12-17T00:00:00Z","timestamp":1418774400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Diabetes"],"published-print":{"date-parts":[[2015,9]]},"abstract":"Abstract<\/jats:title>Objective<\/jats:title>Dipeptidyl peptidase\u20104 (DPP<\/jats:styled-content>\u20104) is responsible for degradation of glucagon\u2010like peptide 1 (GLP<\/jats:styled-content>\u20101) and gastric inhibitory polypeptide (GIP<\/jats:styled-content>), the endogenous incretins that stimulate glucose\u2010dependent insulin secretion. The objective was to evaluate preclinical profile of a novel DPP<\/jats:styled-content>\u20104 inhibitor ZYDPLA1<\/jats:styled-content>.<\/jats:p><\/jats:sec>Methods<\/jats:title>In vitro<\/jats:italic> inhibition potency and selectivity were assessed using recombinant enzymes and\/or plasma. In vivo<\/jats:italic> efficacy was determined in oral glucose tolerance test or mixed meal tolerance test in C57BL<\/jats:styled-content>\/6J<\/jats:styled-content> mice, db\/db mice and Z<\/jats:styled-content>ucker fatty rats. Pharmacokinetics\/pharmacodynamics was studied in mice, rats, dogs, and non\u2010human primates.<\/jats:p><\/jats:sec>Results<\/jats:title>ZYDPLA1<\/jats:styled-content> is a potent, competitive and long acting inhibitor of DPP<\/jats:styled-content>\u20104 (Ki 0.0027\u2009\u03bc<\/jats:italic>M; Koff 2.3\u2009\u00d7\u200910\u20134\u2009<\/jats:sup>s\u20131<\/jats:sup>). ZYDPLA1<\/jats:styled-content> was more than 7000\u2010fold selective for recombinant DPP<\/jats:styled-content>\u20104 relative to DPP<\/jats:styled-content>\u20108 and DPP<\/jats:styled-content>\u20109, and more than 60\u2009000\u2010fold selective relative to fibroblast activation protein (FAP<\/jats:styled-content>) in vitro<\/jats:italic>. DPP<\/jats:styled-content>\u20104 inhibition was comparable across species. In vivo<\/jats:italic>, oral ZYDPLA1<\/jats:styled-content> elevated circulating GLP<\/jats:styled-content>\u20101 and insulin levels in mice and rats and showed dose\u2010dependent anti\u2010hyperglycemic effect. Anti\u2010hyperglycemic effect was also observed in db\/db mice and Zucker fatty rats. ZYDPLA1<\/jats:styled-content> showed low clearance, large volume of distribution, and a long half\u2010life with excellent oral bioavailability in all species. It significantly inhibited plasma DPP<\/jats:styled-content>\u20104 activity in mice and rats for more than 48\u2009h, and for up to 168\u2009h in dogs and non\u2010human primates. Allometric scaling predicted a half\u2010life in humans of 53 to 166\u2009h.<\/jats:p><\/jats:sec>Conclusion<\/jats:title>ZYDPLA1<\/jats:styled-content> is a potent, selective, long\u2010acting oral DPP<\/jats:styled-content>\u20104 inhibitor with potential to become once\u2010a\u2010week therapy for treatment of type 2 diabetes mellitus.<\/jats:p><\/jats:sec>","DOI":"10.1111\/1753-0407.12233","type":"journal-article","created":{"date-parts":[[2014,10,18]],"date-time":"2014-10-18T11:31:11Z","timestamp":1413631871000},"page":"708-717","update-policy":"http:\/\/dx.doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Pharmacological characterization of ZYDPLA1<\/scp>, a novel long\u2010acting dipeptidyl peptidase\u20104 inhibitor"],"prefix":"10.1111","volume":"7","author":[{"given":"Mukul R.","family":"Jain","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology Zydus Research Centre Ahmedabad India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amit A.","family":"Joharapurkar","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology Zydus Research Centre Ahmedabad India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rajesh H.","family":"Bahekar","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry Zydus Research Centre Ahmedabad India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Harilal","family":"Patel","sequence":"additional","affiliation":[{"name":"Department of Drug Metabolism and Pharmacokinetics Zydus Research Centre Ahmedabad India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pradip","family":"Jadav","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry Zydus Research Centre Ahmedabad India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samadhan G.","family":"Kshirsagar","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology Zydus Research Centre Ahmedabad India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vishal J.","family":"Patel","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology Zydus Research Centre Ahmedabad India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kartikkumar N.","family":"Patel","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology Zydus Research Centre Ahmedabad India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vikram K.","family":"Ramanathan","sequence":"additional","affiliation":[{"name":"Department of Drug Metabolism and Pharmacokinetics Zydus Research Centre Ahmedabad India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pankaj R.","family":"Patel","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology Zydus Research Centre Ahmedabad India"},{"name":"Department of Medicinal Chemistry Zydus Research Centre Ahmedabad India"},{"name":"Department of Drug Metabolism and Pharmacokinetics Zydus Research Centre Ahmedabad India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ranjit C.","family":"Desai","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry Zydus Research Centre Ahmedabad India"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2014,12,17]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(11)60679-X"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-147-6-200709180-00178"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2009.11.001"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1463-1326.2008.01018.x"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12325-014-0101-4"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s001250050613"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.2337\/diacare.22.7.1137"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-013-2953-6"},{"key":"e_1_2_8_10_1","doi-asserted-by":"crossref","first-page":"3596","DOI":"10.1016\/S0021-9258(18)94108-6","article-title":"Primary structure of rat liver dipeptidyl peptidase IV deduced from its cDNA and identification of the NH2\u2010terminal signal sequence as the membrane\u2010anchoring domain","volume":"264","author":"Ogata S","year":"1989","journal-title":"J Biol Chem"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1185\/030079906X162746"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.2337\/db10-1707"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.107.135723"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1734-1140(09)70147-1"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2007.05.015"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/9780470715253.ch9"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13300-013-0034-y"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.54.10.2988"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1463-1326.2008.00860.x"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-006-0416-z"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.2337\/db07-1202"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm401992e"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-8587(13)70149-9"}],"container-title":["Journal of Diabetes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2F1753-0407.12233","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/1753-0407.12233","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,24]],"date-time":"2023-09-24T07:55:58Z","timestamp":1695542158000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/1753-0407.12233"}},"subtitle":["\u4e00\u79cd\u65b0\u578b\u7684\u957f\u6548\u4e8c\u80bd\u57fa\u80bd\u9176\u20104\u6291\u5236\u5242ZYDPLA1\u7684\u836f\u7406\u7279\u6027"],"short-title":[],"issued":{"date-parts":[[2014,12,17]]},"references-count":22,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2015,9]]}},"alternative-id":["10.1111\/1753-0407.12233"],"URL":"https:\/\/doi.org\/10.1111\/1753-0407.12233","archive":["Portico"],"relation":{},"ISSN":["1753-0393","1753-0407"],"issn-type":[{"value":"1753-0393","type":"print"},{"value":"1753-0407","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,12,17]]},"assertion":[{"value":"2014-07-02","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2014-09-29","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2014-12-17","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}