{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T10:54:24Z","timestamp":1791024864124,"version":"4.1.0"},"reference-count":43,"publisher":"American Society for Microbiology","issue":"2","license":[{"start":{"date-parts":[[2014,2,1]],"date-time":"2014-02-01T00:00:00Z","timestamp":1391212800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2014,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            GS-9451 is a selective hepatitis C virus (HCV) NS3 protease inhibitor in development for the treatment of genotype 1 (GT1) HCV infection. Key preclinical properties of GS-9451, including\n            <jats:italic>in vitro<\/jats:italic>\n            antiviral activity, selectivity, cross-resistance, and combination activity, as well as pharmacokinetic properties, were determined. In multiple GT1a and GT1b replicon cell lines, GS-9451 had mean 50% effective concentrations (EC\n            <jats:sub>50<\/jats:sub>\n            s) of 13 and 5.4 nM, respectively, with minimal cytotoxicity; similar potency was observed in chimeric replicons encoding the NS3 protease gene of GT1 clinical isolates. GS-9451 was less active in GT2a replicon cells (EC\n            <jats:sub>50<\/jats:sub>\n            = 316 nM). Additive to synergistic\n            <jats:italic>in vitro<\/jats:italic>\n            antiviral activity was observed when GS-9451 was combined with other agents, including alpha interferon, ribavirin, and the polymerase inhibitors GS-6620 and tegobuvir (GS-9190), as well as the NS5A inhibitor ledipasvir (GS-5885). GS-9451 retained wild-type activity against multiple classes of NS5B and NS5A inhibitor resistance mutations. GS-9451 was stable in hepatic microsomes and hepatocytes from human and three other tested species. Systemic clearance was low in dogs and monkeys but high in rats. GS-9451 showed good oral bioavailability in all three species tested. In rats, GS-9451 levels were \u223c40-fold higher in liver than plasma after intravenous dosing, and elimination of GS-9451 was primarily through biliary excretion. Together, these results are consistent with the antiviral activity observed in a recent phase 1b study. The results of\n            <jats:italic>in vitro<\/jats:italic>\n            cross-resistance and combination antiviral assays support the ongoing development of GS-9451 in combination with other agents for the treatment of chronic HCV infection.\n          <\/jats:p>","DOI":"10.1128\/aac.00487-13","type":"journal-article","created":{"date-parts":[[2013,8,13]],"date-time":"2013-08-13T03:35:50Z","timestamp":1376364950000},"page":"647-653","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":30,"title":["Preclinical Characterization of the Novel Hepatitis C Virus NS3 Protease Inhibitor GS-9451"],"prefix":"10.1128","volume":"58","author":[{"given":"Huiling","family":"Yang","sequence":"first","affiliation":[{"name":"Gilead Sciences, Foster City, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret","family":"Robinson","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Foster City, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amoreena C.","family":"Corsa","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Foster City, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Betty","family":"Peng","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Foster City, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guofeng","family":"Cheng","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Foster City, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Tian","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Foster City, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujin","family":"Wang","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Foster City, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rowchanak","family":"Pakdaman","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Foster City, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marian","family":"Shen","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Foster City, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoping","family":"Qi","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Foster City, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongmei","family":"Mo","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Foster City, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chin","family":"Tay","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Foster City, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steve","family":"Krawczyk","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Foster City, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"X. 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