Journal of Medicinal Chemistry · 2009 · 17 citations · 33 references
MedicinePharmacokineticsPharmacologyDrug DiscoveryMolecular VirologyVirologyAntiviral AgentsAntiviral PharmacologyAntiviral TherapyEnzyme InhibitionViral HepatitisViral Hepatitis TreatmentAntiviral Structure-activity RelationshipsBiological CharacterizationDrug Elimination Half-lifeHepatitis C Virus ReplicationOral Drug BioavailabilityViral Polymerase InhibitorsViral Replication InhibitorsVirus Genotypes
The hepatitis C virus (HCV) NS5B polymerase is essential for viral replication and has been a prime target for drug discovery research. Our efforts directed toward the discovery of HCV polymerase inhibitors resulted in the identification of unsymmetrical dialkyl-hydroxynaphthalenoyl-benzothiadiazines 2 and 3. The most active compound displayed activity in genotypes 1a and 1b polymerase and replicon cell culture inhibition assays at subnanomolar and low nanomolar concentrations, respectively. It also displayed an excellent pharmacokinetic profile in rats, with a plasma elimination half-life after intravenous dosing of 4.5 h, oral bioavailability of 77%, and a peak liver concentration of 21.8 microg/mL.
33
Isolation of a cDNA cLone Derived from a Blood-Borne Non-A, Non-B Viral Hepatitis Genome
Qui‐Lim Choo, George Kuo, Amy J. Weiner et al. · Science · 1989 · 6.9K citations
An Assay for Circulating Antibodies to a Major Etiologic Virus of Human Non-A, Non-B Hepatitis
George Kuo, Q L Choo, Harrison Alter et al. · Science · 1989 · 3.4K citations
Replication of Subgenomic Hepatitis C Virus RNAs in a Hepatoma Cell Line
Volker Lohmann, Frank Körner, Jan Oliver Koch et al. · Science · 1999 · 2.8K citations