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Structure-based design, synthesis, and biological evaluation of 1,1-dioxoisothiazole and benzo[b]thiophene-1,1-dioxide derivatives as novel inhibitors of hepatitis C virus NS5B polymerase.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2008 Jul 15; Vol. 18 (14), pp. 4181-5. Date of Electronic Publication: 2008 May 24. - Publication Year :
- 2008
-
Abstract
- A novel series of HCV NS5B polymerase inhibitors comprising 1,1-dioxoisothiazoles and benzo[b]thiophene-1,1-dioxides were designed, synthesized, and evaluated. SAR studies guided by structure-based design led to the identification of a number of potent NS5B inhibitors with nanomolar IC(50) values. The most potent compound exhibited IC(50) less than 10nM against the genotype 1b HCV polymerase and EC(50) of 70 nM against a genotype 1b replicon in cell culture. The DMPK properties of selected compounds were also evaluated.
- Subjects :
- Chemistry, Pharmaceutical methods
Crystallography, X-Ray methods
Drug Design
Genotype
Humans
Inhibitory Concentration 50
Models, Chemical
Molecular Conformation
RNA, Viral metabolism
Structure-Activity Relationship
Thiazoles pharmacokinetics
Thiophenes pharmacokinetics
Antiviral Agents chemical synthesis
Antiviral Agents pharmacokinetics
Enzyme Inhibitors pharmacokinetics
Thiazoles chemical synthesis
Thiophenes chemical synthesis
Viral Nonstructural Proteins antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 18
- Issue :
- 14
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 18554907
- Full Text :
- https://doi.org/10.1016/j.bmcl.2008.05.083