{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T08:44:18Z","timestamp":1788425058995,"version":"build-2803163510"},"reference-count":35,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2019,9,4]],"date-time":"2019-09-04T00:00:00Z","timestamp":1567555200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008373","name":"Takeda Pharmaceutical Company","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008373","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pharmacology Res &amp; Perspec"],"published-print":{"date-parts":[[2019,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Enteropeptidase, localized into the duodenum brush border, is a key enzyme catalyzing the conversion of pancreatic trypsinogen proenzyme to active trypsin, thereby regulating protein digestion and energy homeostasis. We report the discovery and pharmacological profiles of <jats:styled-content style=\"fixed-case\">SCO<\/jats:styled-content>\u2010792, a novel inhibitor of enteropeptidase. A screen employing fluorescence resonance energy transfer was performed to identify enteropeptidase inhibitors. Inhibitory profiles were determined by in vitro assays. To evaluate the in vivo inhibitory effect on protein digestion, an oral protein challenge test was performed in rats. Our screen identified a series of enteropeptidase inhibitors, and compound optimization resulted in identification of <jats:styled-content style=\"fixed-case\">SCO<\/jats:styled-content>\u2010792, which inhibited enteropeptidase activity in vitro, with <jats:styled-content style=\"fixed-case\">IC<\/jats:styled-content><jats:sub>50<\/jats:sub> values of 4.6 and 5.4\u00a0nmol\/L in rats and humans, respectively. In vitro inhibition of enteropeptidase by <jats:styled-content style=\"fixed-case\">SCO<\/jats:styled-content>\u2010792 was potentiated by increased incubation time, and the calculated <jats:italic>K<\/jats:italic><jats:sub>inact<\/jats:sub>\/<jats:styled-content style=\"fixed-case\">K<jats:sub>I<\/jats:sub><\/jats:styled-content> was 82\u00a0000\/mol\/L\u00a0s. An in vitro dissociation assay showed that <jats:styled-content style=\"fixed-case\">SCO<\/jats:styled-content>\u2010792 had a dissociation half\u2010life of almost 14\u00a0hour, with a calculated <jats:italic>k<\/jats:italic><jats:sub>off<\/jats:sub> rate of 0.047\/hour, which suggested that <jats:styled-content style=\"fixed-case\">SCO<\/jats:styled-content>\u2010792 is a reversible enteropeptidase inhibitor. In normal rats, a \u22644\u00a0hour prior oral dose of <jats:styled-content style=\"fixed-case\">SCO<\/jats:styled-content>\u2010792 effectively inhibited plasma elevation of branched\u2010chain amino acids in an oral protein challenge test, which indicated that <jats:styled-content style=\"fixed-case\">SCO<\/jats:styled-content>\u2010792 effectively inhibited protein digestion in vivo. In conclusion, our new screen system identified <jats:styled-content style=\"fixed-case\">SCO<\/jats:styled-content>\u2010792 as a potent and reversible inhibitor against enteropeptidase. <jats:styled-content style=\"fixed-case\">SCO<\/jats:styled-content>\u2010792 slowly dissociated from enteropeptidase in vitro and inhibited protein digestion in vivo. Further study using <jats:styled-content style=\"fixed-case\">SCO<\/jats:styled-content>\u2010792 could reveal the effects of inhibiting enteropeptidase on biological actions.<\/jats:p>","DOI":"10.1002\/prp2.517","type":"journal-article","created":{"date-parts":[[2019,9,5]],"date-time":"2019-09-05T05:24:12Z","timestamp":1567661052000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Discovery and characterization of a small\u2010molecule enteropeptidase inhibitor, <scp>SCO<\/scp>\u2010792"],"prefix":"10.1002","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7120-2211","authenticated-orcid":false,"given":"Masako","family":"Sasaki","sequence":"first","affiliation":[{"name":"Research Takeda Pharmaceutical Company Limited Fujisawa Kanagawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ikuo","family":"Miyahisa","sequence":"additional","affiliation":[{"name":"Research Takeda Pharmaceutical Company Limited Fujisawa Kanagawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sachiko","family":"Itono","sequence":"additional","affiliation":[{"name":"Research Takeda Pharmaceutical Company Limited Fujisawa Kanagawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroaki","family":"Yashiro","sequence":"additional","affiliation":[{"name":"Research Takeda Pharmaceutical Company Limited Fujisawa Kanagawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideyuki","family":"Hiyoshi","sequence":"additional","affiliation":[{"name":"Research Takeda Pharmaceutical Company Limited Fujisawa Kanagawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazue","family":"Tsuchimori","sequence":"additional","affiliation":[{"name":"Research Takeda Pharmaceutical Company Limited Fujisawa Kanagawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken\u2010ichi","family":"Hamagami","sequence":"additional","affiliation":[{"name":"Research Takeda Pharmaceutical Company Limited Fujisawa Kanagawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5252-6264","authenticated-orcid":false,"given":"Yusuke","family":"Moritoh","sequence":"additional","affiliation":[{"name":"SCOHIA PHARMA, Inc. 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