{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T10:37:57Z","timestamp":1789641477598,"version":"4.0.0"},"reference-count":38,"publisher":"SAGE Publications","issue":"5","license":[{"start":{"date-parts":[[2016,7,1]],"date-time":"2016-07-01T00:00:00Z","timestamp":1467331200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Antiviral Therapy"],"published-print":{"date-parts":[[2017,7]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>GS-9256 is an inhibitor of HCV NS3 protease with a macrocyclic structure and novel phosphinic acid pharmacophore.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Key preclinical properties of GS-9256 including in vitro antiviral activity, cross-resistance and pharmacokinetic properties were investigated in non-human species.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In genotype (GT) 1b Huh-luc cells with a replicon encoding luciferase, GS-9256 had a mean 50% effective concentration (EC\n                      <jats:sub>50<\/jats:sub>\n                      ) value of 20.0 nM, with minimal cytotoxicity. Antiviral activity was similar in a number of additional GT1b and GT1a replicon cell lines. Similar potency was observed in chimeric replicons encoding the NS3 protease of GT1 clinical isolates. GS-9256 was less active in GT2a replicon cells (14.2-fold increase in EC\n                      <jats:sub>50<\/jats:sub>\n                      ). Additive to synergistic in vitro antiviral activity was observed when GS-9256 was combined with other agents including interferon-\u03b1, ribavirin, NS5B polymerase inhibitors GS-6620 and tegobuvir, as well as the NS5A inhibitor ledipasvir. GS-9256 retained wild-type activity against all tested NS5B and NS5A inhibitor resistance mutations. GS-9256 was metabolically stable in microsomes and hepatocytes of tested species, including rodents, dogs and humans. GS-9256 had high bioavailability in mice (near 100%) and moderate bioavailability in rats (14%), dogs (21%) and monkeys (14%). Elimination half-lives were approximately 2 h in mice, 0.6 h in rats, 5 h in dogs and 4 h in monkey. A study in bile duct-cannulated rats indicated that the major route of elimination is through biliary excretion of unmetabolized GS-9256.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>GS-9256 showed a favourable preclinical profile supportive of clinical development for the treatment of chronic HCV infection in GT1 patients.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3851\/imp3132","type":"journal-article","created":{"date-parts":[[2017,1,20]],"date-time":"2017-01-20T05:22:52Z","timestamp":1484889772000},"page":"413-420","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":7,"title":["Preclinical Characterization of the Novel HCV NS3 Protease Inhibitor GS-9256"],"prefix":"10.1177","volume":"22","author":[{"given":"Huiling","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Biology, Gilead Sciences, Foster City, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Drug Metabolism, Gilead Sciences, Foster City, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Drug Metabolism, Gilead Sciences, Foster City, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerry","family":"Rhodes","sequence":"additional","affiliation":[{"name":"Department of Drug Metabolism, Gilead Sciences, Foster City, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret","family":"Robinson","sequence":"additional","affiliation":[{"name":"Department of Biology, Gilead Sciences, Foster City, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guofeng","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Biology, Gilead Sciences, Foster City, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoping","family":"Qi","sequence":"additional","affiliation":[{"name":"Department of Biology, Gilead Sciences, Foster City, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongmei","family":"Mo","sequence":"additional","affiliation":[{"name":"Department of Biology, Gilead Sciences, Foster City, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Tian","sequence":"additional","affiliation":[{"name":"Department of Biology, Gilead Sciences, Foster City, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rowchanak","family":"Pakdaman","sequence":"additional","affiliation":[{"name":"Department of Formulation and Process Development, Gilead Sciences, Foster City, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"X Christopher","family":"Sheng","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Gilead Sciences, Foster City, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Choung U","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Gilead Sciences, Foster City, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"IV","given":"William E","family":"Delaney","sequence":"additional","affiliation":[{"name":"Department of Biology, Gilead Sciences, Foster City, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2016,7,1]]},"reference":[{"key":"bibr1-IMP3132","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.72.8.6758-6769.1998"},{"key":"bibr2-IMP3132","doi-asserted-by":"publisher","DOI":"10.1038\/nature04077"},{"key":"bibr3-IMP3132","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0408824102"},{"key":"bibr4-IMP3132","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0508531102"},{"key":"bibr5-IMP3132","doi-asserted-by":"publisher","DOI":"10.1038\/nature02099"},{"key":"bibr6-IMP3132","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1213651"},{"key":"bibr7-IMP3132","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1306227"},{"key":"bibr8-IMP3132","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(14)61036-9"},{"key":"bibr9-IMP3132","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2011.12.038"},{"key":"bibr10-IMP3132","unstructured":"Goldwater R., DeMicco M., Zong J. Safety, pharmacokinetics and antiviral activity of single oral doses of the HCV NS3 protease inhibitor GS-9256.\n                      61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD)\n                      . 29 October\u20132 November 2010, Boston, MA, USA. 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