{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T17:55:26Z","timestamp":1759341326093,"version":"3.41.2"},"reference-count":48,"publisher":"American Society for Microbiology","issue":"1","license":[{"start":{"date-parts":[[2017,1,1]],"date-time":"2017-01-01T00:00:00Z","timestamp":1483228800000},"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":[[2017,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>\n            The current paradigm for the treatment of chronic hepatitis C virus (HCV) infection involves combinations of agents that act directly on steps of the HCV life cycle. Here we report the preclinical characteristics of ITMN-8187, a nonmacrocyclic inhibitor of the NS3\/4A HCV protease. X-ray crystallographic studies of ITMN-8187 and simeprevir binding to NS3\/4A protease demonstrated good agreement between structures. Low nanomolar biochemical potency was maintained against NS3\/4A derived from HCV genotypes 1, 2b, 4, 5, and 6. In cell-based potency assays, half-maximal reduction of genotype 1a and 1b HCV replicon RNA was afforded by 11 and 4 nM doses of ITMN-8187, respectively. Combinations of ITMN-8187 with other directly acting antiviral agents\n            <jats:italic>in vitro<\/jats:italic>\n            displayed additive antiviral efficacy. A 30-mg\/kg of body weight dose of ITMN-8187 administered for 4 days yielded significant viral load reductions through day 5 in a chimeric mouse model of HCV. A 3-mg\/kg oral dose administered to rats, dogs, or monkeys yielded concentrations in plasma 16 h after dosing that exceeded the half-maximal effective concentration of ITMN-8187. Human microdose pharmacokinetics showed low intersubject variability and prolonged oral absorption with first-order elimination kinetics compatible with once-daily dosing. These preclinical characteristics compare favorably with those of other NS3\/4A inhibitors approved for the treatment of chronic HCV infection.\n          <\/jats:p>","DOI":"10.1128\/aac.01569-16","type":"journal-article","created":{"date-parts":[[2016,10,18]],"date-time":"2016-10-18T20:21:15Z","timestamp":1476822075000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":4,"title":["Preclinical Characterization and Human Microdose Pharmacokinetics of ITMN-8187, a Nonmacrocyclic Inhibitor of the Hepatitis C Virus NS3 Protease"],"prefix":"10.1128","volume":"61","author":[{"given":"Ravi","family":"Rajagopalan","sequence":"first","affiliation":[{"name":"InterMune Incorporated, Brisbane, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lin","family":"Pan","sequence":"additional","affiliation":[{"name":"InterMune Incorporated, Brisbane, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caralee","family":"Schaefer","sequence":"additional","affiliation":[{"name":"InterMune Incorporated, Brisbane, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Nicholas","sequence":"additional","affiliation":[{"name":"InterMune Incorporated, Brisbane, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sharlene","family":"Lim","sequence":"additional","affiliation":[{"name":"InterMune Incorporated, Brisbane, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shawn","family":"Misialek","sequence":"additional","affiliation":[{"name":"InterMune Incorporated, Brisbane, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah","family":"Stevens","sequence":"additional","affiliation":[{"name":"InterMune Incorporated, Brisbane, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lisa","family":"Hooi","sequence":"additional","affiliation":[{"name":"InterMune Incorporated, Brisbane, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natalia","family":"Aleskovski","sequence":"additional","affiliation":[{"name":"InterMune Incorporated, Brisbane, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Donald","family":"Ruhrmund","sequence":"additional","affiliation":[{"name":"InterMune Incorporated, Brisbane, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karl","family":"Kossen","sequence":"additional","affiliation":[{"name":"InterMune Incorporated, Brisbane, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lea","family":"Huang","sequence":"additional","affiliation":[{"name":"InterMune Incorporated, Brisbane, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sophia","family":"Yap","sequence":"additional","affiliation":[{"name":"InterMune Incorporated, Brisbane, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leonid","family":"Beigelman","sequence":"additional","affiliation":[{"name":"InterMune Incorporated, Brisbane, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vladimir","family":"Serebryany","sequence":"additional","affiliation":[{"name":"InterMune Incorporated, Brisbane, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jyanwei","family":"Liu","sequence":"additional","affiliation":[{"name":"InterMune Incorporated, Brisbane, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Srikonda","family":"Sastry","sequence":"additional","affiliation":[{"name":"InterMune Incorporated, Brisbane, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Scott","family":"Seiwert","sequence":"additional","affiliation":[{"name":"InterMune Incorporated, Brisbane, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brad","family":"Buckman","sequence":"additional","affiliation":[{"name":"InterMune Incorporated, Brisbane, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"unstructured":"World Health Organization. July2016. Hepatitis C fact sheet. http:\/\/www.who.int\/mediacentre\/factsheets\/fs164\/en.","key":"e_1_3_2_2_2"},{"unstructured":"Centers for Disease Control and Prevention. May2015. Hepatitis C information. http:\/\/www.cdc.gov\/hepatitis\/HCV\/.","key":"e_1_3_2_3_2"},{"unstructured":"Centers for Disease Control and Prevention. June 2012. Viral hepatitis statistics and surveillance: number and rate of deaths with hepatitis C listed as a cause of death by demographic characteristic and year\u2014United States 2004-2008. http:\/\/www.cdc.gov\/hepatitis\/Statistics\/2010Surveillance\/Table4.5.htm\n.","key":"e_1_3_2_4_2"},{"doi-asserted-by":"publisher","key":"e_1_3_2_5_2","DOI":"10.1073\/pnas.88.6.2451"},{"doi-asserted-by":"publisher","key":"e_1_3_2_6_2","DOI":"10.1073\/pnas.90.22.10583"},{"doi-asserted-by":"publisher","key":"e_1_3_2_7_2","DOI":"10.1128\/jvi.67.8.4665-4675.1993"},{"doi-asserted-by":"publisher","key":"e_1_3_2_8_2","DOI":"10.1073\/pnas.88.13.5547"},{"doi-asserted-by":"publisher","key":"e_1_3_2_9_2","DOI":"10.1016\/S0065-3527(04)63002-8"},{"doi-asserted-by":"publisher","key":"e_1_3_2_10_2","DOI":"10.1038\/nature04077"},{"doi-asserted-by":"publisher","key":"e_1_3_2_11_2","DOI":"10.1136\/gut.2010.232116"},{"doi-asserted-by":"publisher","key":"e_1_3_2_12_2","DOI":"10.1126\/science.1082604"},{"doi-asserted-by":"publisher","key":"e_1_3_2_13_2","DOI":"10.1021\/bi980313v"},{"doi-asserted-by":"publisher","key":"e_1_3_2_14_2","DOI":"10.1056\/NEJMoa1009482"},{"doi-asserted-by":"publisher","key":"e_1_3_2_15_2","DOI":"10.1056\/NEJMoa1012912"},{"doi-asserted-by":"publisher","key":"e_1_3_2_16_2","DOI":"10.1056\/NEJMoa1010494"},{"doi-asserted-by":"publisher","key":"e_1_3_2_17_2","DOI":"10.1056\/NEJMoa1013086"},{"key":"e_1_3_2_18_2","volume-title":"Incivek package insert","author":"Vertex Pharmaceuticals","year":"2013","unstructured":"Vertex Pharmaceuticals. 2013. 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