In Vitro and In Vivo Isotope Effects with Hepatitis C Protease Inhibitors: Enhanced Plasma Exposure of Deuterated Telaprevir versus Telaprevir in Rats
Telaprevir 2 (VX-950), an inhibitor of the hepatitis C virus (HCVa) NS3-4A protease, is in phase 3 clinical trials. One of the major metabolites of 2 is its P1-(R)-diastereoisomer, 3 (VRT-394), containing an inversion at the chiral center next to the α-ketoamide on exchange of a proton with solvent....
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| Veröffentlicht in: | Journal of medicinal chemistry 2009-12, Vol.52 (24), p.7993-8001 |
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| creator | Maltais, François Jung, Young Chun Chen, Minzhang Tanoury, Jerry Perni, Robert B Mani, Nagraj Laitinen, Leena Huang, Hui Liao, Shengkai Gao, Hongying Tsao, Hong Block, Eric Ma, Chien Shawgo, Rebecca S Town, Christopher Brummel, Christopher L Howe, David Pazhanisamy, S Raybuck, Scott Namchuk, Mark Bennani, Youssef L |
| description | Telaprevir 2 (VX-950), an inhibitor of the hepatitis C virus (HCVa) NS3-4A protease, is in phase 3 clinical trials. One of the major metabolites of 2 is its P1-(R)-diastereoisomer, 3 (VRT-394), containing an inversion at the chiral center next to the α-ketoamide on exchange of a proton with solvent. Compound 3 is approximately 30-fold less active against HCV protease. In an attempt to suppress the epimerization of 2 without losing activity against the HCV protease, the proton at that chiral site was replaced with deuterium (d). The compound 1 (d-telaprevir) is as efficacious as 2 in in vitro inhibition of protease activity and viral replication (replicon) assays. The kinetics of in vitro stability of 1 and 2 in buffered pH solutions and plasma samples, including human plasma, suggest that 1 is significantly more stable than 2. Oral administration (10 mg/kg) in rats resulted in a ∼13% increase of AUC for 1. |
| doi_str_mv | 10.1021/jm901023f |
| format | Article |
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One of the major metabolites of 2 is its P1-(R)-diastereoisomer, 3 (VRT-394), containing an inversion at the chiral center next to the α-ketoamide on exchange of a proton with solvent. Compound 3 is approximately 30-fold less active against HCV protease. In an attempt to suppress the epimerization of 2 without losing activity against the HCV protease, the proton at that chiral site was replaced with deuterium (d). The compound 1 (d-telaprevir) is as efficacious as 2 in in vitro inhibition of protease activity and viral replication (replicon) assays. The kinetics of in vitro stability of 1 and 2 in buffered pH solutions and plasma samples, including human plasma, suggest that 1 is significantly more stable than 2. Oral administration (10 mg/kg) in rats resulted in a ∼13% increase of AUC for 1.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm901023f</identifier><identifier>PMID: 19894743</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Columbus, OH: American Chemical Society</publisher><subject>Administration, Oral ; Animals ; Antibiotics. Antiinfectious agents. Antiparasitic agents ; Antiviral agents ; Antiviral Agents - blood ; Antiviral Agents - chemical synthesis ; Antiviral Agents - chemistry ; Antiviral Agents - pharmacokinetics ; Biological and medical sciences ; Buffers ; Deuterium - chemistry ; Dogs ; Drug Stability ; Hepacivirus - enzymology ; Humans ; Hydrogen-Ion Concentration ; Injections, Intravenous ; Isotope Labeling ; Medical sciences ; Oligopeptides - blood ; Oligopeptides - chemical synthesis ; Oligopeptides - chemistry ; Oligopeptides - pharmacokinetics ; Pharmacology. Drug treatments ; Rats ; Serine Proteinase Inhibitors - blood ; Serine Proteinase Inhibitors - chemical synthesis ; Serine Proteinase Inhibitors - chemistry ; Serine Proteinase Inhibitors - pharmacokinetics ; Stereoisomerism ; Viral Nonstructural Proteins - antagonists & inhibitors</subject><ispartof>Journal of medicinal chemistry, 2009-12, Vol.52 (24), p.7993-8001</ispartof><rights>Copyright © 2009 American Chemical Society</rights><rights>2015 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a344t-70ef6deeaa12f2f1067db5d644d4fc6842e53512e40435033a0cec34c6d0440f3</citedby><cites>FETCH-LOGICAL-a344t-70ef6deeaa12f2f1067db5d644d4fc6842e53512e40435033a0cec34c6d0440f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm901023f$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm901023f$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2765,27076,27924,27925,56738,56788</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=22244978$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19894743$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Maltais, François</creatorcontrib><creatorcontrib>Jung, Young Chun</creatorcontrib><creatorcontrib>Chen, Minzhang</creatorcontrib><creatorcontrib>Tanoury, Jerry</creatorcontrib><creatorcontrib>Perni, Robert B</creatorcontrib><creatorcontrib>Mani, Nagraj</creatorcontrib><creatorcontrib>Laitinen, Leena</creatorcontrib><creatorcontrib>Huang, Hui</creatorcontrib><creatorcontrib>Liao, Shengkai</creatorcontrib><creatorcontrib>Gao, Hongying</creatorcontrib><creatorcontrib>Tsao, Hong</creatorcontrib><creatorcontrib>Block, Eric</creatorcontrib><creatorcontrib>Ma, Chien</creatorcontrib><creatorcontrib>Shawgo, Rebecca S</creatorcontrib><creatorcontrib>Town, Christopher</creatorcontrib><creatorcontrib>Brummel, Christopher L</creatorcontrib><creatorcontrib>Howe, David</creatorcontrib><creatorcontrib>Pazhanisamy, S</creatorcontrib><creatorcontrib>Raybuck, Scott</creatorcontrib><creatorcontrib>Namchuk, Mark</creatorcontrib><creatorcontrib>Bennani, Youssef L</creatorcontrib><title>In Vitro and In Vivo Isotope Effects with Hepatitis C Protease Inhibitors: Enhanced Plasma Exposure of Deuterated Telaprevir versus Telaprevir in Rats</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Telaprevir 2 (VX-950), an inhibitor of the hepatitis C virus (HCVa) NS3-4A protease, is in phase 3 clinical trials. One of the major metabolites of 2 is its P1-(R)-diastereoisomer, 3 (VRT-394), containing an inversion at the chiral center next to the α-ketoamide on exchange of a proton with solvent. Compound 3 is approximately 30-fold less active against HCV protease. In an attempt to suppress the epimerization of 2 without losing activity against the HCV protease, the proton at that chiral site was replaced with deuterium (d). The compound 1 (d-telaprevir) is as efficacious as 2 in in vitro inhibition of protease activity and viral replication (replicon) assays. The kinetics of in vitro stability of 1 and 2 in buffered pH solutions and plasma samples, including human plasma, suggest that 1 is significantly more stable than 2. Oral administration (10 mg/kg) in rats resulted in a ∼13% increase of AUC for 1.</description><subject>Administration, Oral</subject><subject>Animals</subject><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents</subject><subject>Antiviral agents</subject><subject>Antiviral Agents - blood</subject><subject>Antiviral Agents - chemical synthesis</subject><subject>Antiviral Agents - chemistry</subject><subject>Antiviral Agents - pharmacokinetics</subject><subject>Biological and medical sciences</subject><subject>Buffers</subject><subject>Deuterium - chemistry</subject><subject>Dogs</subject><subject>Drug Stability</subject><subject>Hepacivirus - enzymology</subject><subject>Humans</subject><subject>Hydrogen-Ion Concentration</subject><subject>Injections, Intravenous</subject><subject>Isotope Labeling</subject><subject>Medical sciences</subject><subject>Oligopeptides - blood</subject><subject>Oligopeptides - chemical synthesis</subject><subject>Oligopeptides - chemistry</subject><subject>Oligopeptides - pharmacokinetics</subject><subject>Pharmacology. Drug treatments</subject><subject>Rats</subject><subject>Serine Proteinase Inhibitors - blood</subject><subject>Serine Proteinase Inhibitors - chemical synthesis</subject><subject>Serine Proteinase Inhibitors - chemistry</subject><subject>Serine Proteinase Inhibitors - pharmacokinetics</subject><subject>Stereoisomerism</subject><subject>Viral Nonstructural Proteins - antagonists & inhibitors</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkU1v1DAQhi0EokvhwB9AviDEITCxnS9u1bLQlSpRocI1mnXGWq-SOHicBf4Iv5dAVy0HTvP1zDvSO0I8z-FNDip_exgaWBLtHohVXijITA3moVgBKJWpUukz8YT5AAA6V_qxOMubujGV0SvxazvKrz7FIHHs5N_iGOSWQwoTyY1zZBPL7z7t5SVNmHzyLNfyOoZEyLRs7P3OpxD5ndyMexwtdfK6Rx5Qbn5MgedIMjj5nuZEEdMyvaEep0hHH-WRIs_8b8eP8jMmfioeOeyZnp3iufjyYXOzvsyuPn3cri-uMtTGpKwCcmVHhJgrp1wOZdXtiq40pjPOlrVRVOgiV2TA6AK0RrBktbFlB8aA0-fi1a3uFMO3mTi1g2dLfY8jhZnbSusSmrouFvL1LWljYI7k2in6AePPNof2zxfauy8s7IuT6rwbqLsnT7YvwMsTgGyxd3HxzfMdp5Qypqnqew4tt4cwx3Ex4z8HfwNjXJxt</recordid><startdate>20091224</startdate><enddate>20091224</enddate><creator>Maltais, François</creator><creator>Jung, Young Chun</creator><creator>Chen, Minzhang</creator><creator>Tanoury, Jerry</creator><creator>Perni, Robert B</creator><creator>Mani, Nagraj</creator><creator>Laitinen, Leena</creator><creator>Huang, Hui</creator><creator>Liao, Shengkai</creator><creator>Gao, Hongying</creator><creator>Tsao, Hong</creator><creator>Block, Eric</creator><creator>Ma, Chien</creator><creator>Shawgo, Rebecca S</creator><creator>Town, Christopher</creator><creator>Brummel, Christopher L</creator><creator>Howe, David</creator><creator>Pazhanisamy, S</creator><creator>Raybuck, Scott</creator><creator>Namchuk, Mark</creator><creator>Bennani, Youssef L</creator><general>American Chemical Society</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20091224</creationdate><title>In Vitro and In Vivo Isotope Effects with Hepatitis C Protease Inhibitors: Enhanced Plasma Exposure of Deuterated Telaprevir versus Telaprevir in Rats</title><author>Maltais, François ; Jung, Young Chun ; Chen, Minzhang ; Tanoury, Jerry ; Perni, Robert B ; Mani, Nagraj ; Laitinen, Leena ; Huang, Hui ; Liao, Shengkai ; Gao, Hongying ; Tsao, Hong ; Block, Eric ; Ma, Chien ; Shawgo, Rebecca S ; Town, Christopher ; Brummel, Christopher L ; Howe, David ; Pazhanisamy, S ; Raybuck, Scott ; Namchuk, Mark ; Bennani, Youssef L</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a344t-70ef6deeaa12f2f1067db5d644d4fc6842e53512e40435033a0cec34c6d0440f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Administration, Oral</topic><topic>Animals</topic><topic>Antibiotics. Antiinfectious agents. Antiparasitic agents</topic><topic>Antiviral agents</topic><topic>Antiviral Agents - blood</topic><topic>Antiviral Agents - chemical synthesis</topic><topic>Antiviral Agents - chemistry</topic><topic>Antiviral Agents - pharmacokinetics</topic><topic>Biological and medical sciences</topic><topic>Buffers</topic><topic>Deuterium - chemistry</topic><topic>Dogs</topic><topic>Drug Stability</topic><topic>Hepacivirus - enzymology</topic><topic>Humans</topic><topic>Hydrogen-Ion Concentration</topic><topic>Injections, Intravenous</topic><topic>Isotope Labeling</topic><topic>Medical sciences</topic><topic>Oligopeptides - blood</topic><topic>Oligopeptides - chemical synthesis</topic><topic>Oligopeptides - chemistry</topic><topic>Oligopeptides - pharmacokinetics</topic><topic>Pharmacology. Drug treatments</topic><topic>Rats</topic><topic>Serine Proteinase Inhibitors - blood</topic><topic>Serine Proteinase Inhibitors - chemical synthesis</topic><topic>Serine Proteinase Inhibitors - chemistry</topic><topic>Serine Proteinase Inhibitors - pharmacokinetics</topic><topic>Stereoisomerism</topic><topic>Viral Nonstructural Proteins - antagonists & inhibitors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Maltais, François</creatorcontrib><creatorcontrib>Jung, Young Chun</creatorcontrib><creatorcontrib>Chen, Minzhang</creatorcontrib><creatorcontrib>Tanoury, Jerry</creatorcontrib><creatorcontrib>Perni, Robert B</creatorcontrib><creatorcontrib>Mani, Nagraj</creatorcontrib><creatorcontrib>Laitinen, Leena</creatorcontrib><creatorcontrib>Huang, Hui</creatorcontrib><creatorcontrib>Liao, Shengkai</creatorcontrib><creatorcontrib>Gao, Hongying</creatorcontrib><creatorcontrib>Tsao, Hong</creatorcontrib><creatorcontrib>Block, Eric</creatorcontrib><creatorcontrib>Ma, Chien</creatorcontrib><creatorcontrib>Shawgo, Rebecca S</creatorcontrib><creatorcontrib>Town, Christopher</creatorcontrib><creatorcontrib>Brummel, Christopher L</creatorcontrib><creatorcontrib>Howe, David</creatorcontrib><creatorcontrib>Pazhanisamy, S</creatorcontrib><creatorcontrib>Raybuck, Scott</creatorcontrib><creatorcontrib>Namchuk, Mark</creatorcontrib><creatorcontrib>Bennani, Youssef L</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Maltais, François</au><au>Jung, Young Chun</au><au>Chen, Minzhang</au><au>Tanoury, Jerry</au><au>Perni, Robert B</au><au>Mani, Nagraj</au><au>Laitinen, Leena</au><au>Huang, Hui</au><au>Liao, Shengkai</au><au>Gao, Hongying</au><au>Tsao, Hong</au><au>Block, Eric</au><au>Ma, Chien</au><au>Shawgo, Rebecca S</au><au>Town, Christopher</au><au>Brummel, Christopher L</au><au>Howe, David</au><au>Pazhanisamy, S</au><au>Raybuck, Scott</au><au>Namchuk, Mark</au><au>Bennani, Youssef L</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>In Vitro and In Vivo Isotope Effects with Hepatitis C Protease Inhibitors: Enhanced Plasma Exposure of Deuterated Telaprevir versus Telaprevir in Rats</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2009-12-24</date><risdate>2009</risdate><volume>52</volume><issue>24</issue><spage>7993</spage><epage>8001</epage><pages>7993-8001</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>Telaprevir 2 (VX-950), an inhibitor of the hepatitis C virus (HCVa) NS3-4A protease, is in phase 3 clinical trials. One of the major metabolites of 2 is its P1-(R)-diastereoisomer, 3 (VRT-394), containing an inversion at the chiral center next to the α-ketoamide on exchange of a proton with solvent. Compound 3 is approximately 30-fold less active against HCV protease. In an attempt to suppress the epimerization of 2 without losing activity against the HCV protease, the proton at that chiral site was replaced with deuterium (d). The compound 1 (d-telaprevir) is as efficacious as 2 in in vitro inhibition of protease activity and viral replication (replicon) assays. The kinetics of in vitro stability of 1 and 2 in buffered pH solutions and plasma samples, including human plasma, suggest that 1 is significantly more stable than 2. Oral administration (10 mg/kg) in rats resulted in a ∼13% increase of AUC for 1.</abstract><cop>Columbus, OH</cop><pub>American Chemical Society</pub><pmid>19894743</pmid><doi>10.1021/jm901023f</doi><tpages>9</tpages></addata></record> |
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| subjects | Administration, Oral Animals Antibiotics. Antiinfectious agents. Antiparasitic agents Antiviral agents Antiviral Agents - blood Antiviral Agents - chemical synthesis Antiviral Agents - chemistry Antiviral Agents - pharmacokinetics Biological and medical sciences Buffers Deuterium - chemistry Dogs Drug Stability Hepacivirus - enzymology Humans Hydrogen-Ion Concentration Injections, Intravenous Isotope Labeling Medical sciences Oligopeptides - blood Oligopeptides - chemical synthesis Oligopeptides - chemistry Oligopeptides - pharmacokinetics Pharmacology. Drug treatments Rats Serine Proteinase Inhibitors - blood Serine Proteinase Inhibitors - chemical synthesis Serine Proteinase Inhibitors - chemistry Serine Proteinase Inhibitors - pharmacokinetics Stereoisomerism Viral Nonstructural Proteins - antagonists & inhibitors |
| title | In Vitro and In Vivo Isotope Effects with Hepatitis C Protease Inhibitors: Enhanced Plasma Exposure of Deuterated Telaprevir versus Telaprevir in Rats |
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