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rdf:type |
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lifeskim:mentions |
umls-concept:C0019196,
umls-concept:C0022262,
umls-concept:C0032105,
umls-concept:C0033607,
umls-concept:C0034693,
umls-concept:C0332157,
umls-concept:C1280500,
umls-concept:C1515655,
umls-concept:C1533691,
umls-concept:C1876229,
umls-concept:C2349975
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pubmed:issue |
24
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pubmed:dateCreated |
2009-12-17
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pubmed:abstractText |
Telaprevir 2 (VX-950), an inhibitor of the hepatitis C virus (HCV(a)) 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 alpha-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 approximately 13% increase of AUC for 1.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Dec
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pubmed:issn |
1520-4804
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pubmed:author |
pubmed-author:BennaniYoussef LYL,
pubmed-author:BlockEricE,
pubmed-author:BrummelChristopher LCL,
pubmed-author:ChenMinzhangM,
pubmed-author:GaoHongyingH,
pubmed-author:HoweDavidD,
pubmed-author:HuangHuiH,
pubmed-author:JungYoung ChunYC,
pubmed-author:LaitinenLeenaL,
pubmed-author:LiaoShengkaiS,
pubmed-author:MaChienC,
pubmed-author:MaltaisFrançoisF,
pubmed-author:ManiNagrajN,
pubmed-author:MittletonM FMF,
pubmed-author:NamchukMarkM,
pubmed-author:PazhanisamySS,
pubmed-author:PerniRobert BRB,
pubmed-author:RaybuckScottS,
pubmed-author:TanouryJerryJ,
pubmed-author:TownChristopherC,
pubmed-author:TsaoHongH
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pubmed:issnType |
Electronic
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pubmed:day |
24
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pubmed:volume |
52
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
7993-8001
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pubmed:meshHeading |
pubmed-meshheading:19894743-Administration, Oral,
pubmed-meshheading:19894743-Animals,
pubmed-meshheading:19894743-Antiviral Agents,
pubmed-meshheading:19894743-Buffers,
pubmed-meshheading:19894743-Deuterium,
pubmed-meshheading:19894743-Dogs,
pubmed-meshheading:19894743-Drug Stability,
pubmed-meshheading:19894743-Hepacivirus,
pubmed-meshheading:19894743-Humans,
pubmed-meshheading:19894743-Hydrogen-Ion Concentration,
pubmed-meshheading:19894743-Injections, Intravenous,
pubmed-meshheading:19894743-Isotope Labeling,
pubmed-meshheading:19894743-Oligopeptides,
pubmed-meshheading:19894743-Rats,
pubmed-meshheading:19894743-Serine Proteinase Inhibitors,
pubmed-meshheading:19894743-Stereoisomerism,
pubmed-meshheading:19894743-Viral Nonstructural Proteins
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pubmed:year |
2009
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pubmed:articleTitle |
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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pubmed:affiliation |
Vertex Pharmaceuticals Incorporated, Cambridge, Massachusetts 02139, USA.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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