ABSTRACT
This letter describes the discovery of a fused benzofuran scaffold viable for preparing a series of novel potent HCV NS5B polymerase non-nucleoside inhibitors. Designed on the basis of the functionalized benzofuran derivative nesbuvir (HCV-796), these compounds presumably bind similarly to the allosteric binding site in the "palm" domain of HCV NS5B protein. SAR of each potential hydrogen-bonding interaction site of this novel scaffold is discussed along with some preliminary genotypic profile and PK data of several advanced compounds.
Subject(s)
Antiviral Agents/pharmacology , Benzofurans/pharmacology , Drug Discovery , Enzyme Inhibitors/pharmacology , HIV/drug effects , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Benzofurans/chemical synthesis , Benzofurans/chemistry , Cell Line, Tumor , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Microbial Sensitivity Tests , Molecular Structure , Rats , Structure-Activity RelationshipABSTRACT
This Letter describes the synthesis, representative structure activity relationship (SAR), activity and PK profiles of a series of functionalized benzimidazole-naphthylene-imidazole derivatives as HCV NS5A inhibitors. This effort successfully led to the discovery of ravidasvir (PPI-668), which has been well tolerated and shown high sustained viral response rates as a key component in all-oral combination regimens in multiple human clinical trials.
Subject(s)
Antiviral Agents/pharmacology , Benzimidazoles/pharmacology , Hepacivirus/drug effects , Valine/analogs & derivatives , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/pharmacokinetics , Area Under Curve , Benzimidazoles/chemistry , Benzimidazoles/pharmacokinetics , Dogs , Drug Discovery , Genotype , Hepacivirus/genetics , Humans , Macaca fascicularis , Rats , Structure-Activity Relationship , Valine/chemistry , Valine/pharmacokinetics , Valine/pharmacologyABSTRACT
This Letter describes the discovery of a number of functionalized bisimidazoles bearing a cyclohexylphenyl, piperidylphenyl, or bicyclo[2,2,2]octylphenyl motif as HCV NS5A inhibitors. Compounds 2c, 4b and 6 have demonstrated low single-digit nM potency in gt-1a replicon and double-digit pM potency in gt-1b replicon, respectively. Moreover, both 4b and 6 have, respectively, exhibited good oral bioavailability in rats with a favorable liver/plasma ratio of the drug concentration.
Subject(s)
Antiviral Agents/chemistry , Drug Discovery , Hydrocarbons, Acyclic/chemistry , Imidazoles/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Virus Replication/drug effects , Animals , Antiviral Agents/pharmacokinetics , Antiviral Agents/pharmacology , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/virology , Drug Evaluation, Preclinical , Hepacivirus/drug effects , Hepatitis C/drug therapy , Hepatitis C/virology , Humans , Liver Neoplasms/drug therapy , Liver Neoplasms/virology , Male , Models, Molecular , Molecular Structure , Rats , Rats, Sprague-Dawley , Replicon/drug effects , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
This Letter describes the synthesis and biological evaluation of a number of functionalized bisimidazoles bearing annulated tricyclic motifs as potent inhibitors of HCV NS5A protein. Compound 4 h, which contains a substituted tricyclic 6-6-6 xanthene, demonstrated broad genotypic spectrum, compelling potency, and good oral bioavailability with dose-dependent drug exposure level in multiple animal species.
