ABSTRACT
A novel unsymmetrical structural class of orally bioavailable hepatitis C virus (HCV) nonstructural 5A protein (NS5A) inhibitors has been generated by improving both the solubility and membrane permeability of the lead compound found in our previous work. The representative compound 14, with a 5-hydroxymethylpyrazine group and a 3-t-butylpropargyl group on each side of the molecule, exhibited the best oral bioavailability in this study, inhibiting not only the HCV genotype 1a, 1b, 2a, and 3a replicons with EC50 values in the picomolar range, but also inhibited 1a Q30 mutants induced by launched symmetrical inhibitors with EC50 values in the low nanomolar range.
Subject(s)
Antiviral Agents/chemistry , Hepacivirus/metabolism , Viral Nonstructural Proteins/antagonists & inhibitors , Administration, Oral , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Genotype , Hepacivirus/genetics , Hepatitis C/drug therapy , Hepatitis C/pathology , Hepatitis C/virology , Humans , Mutation , Pargyline/chemistry , Pyrazines/chemistry , Structure-Activity Relationship , Viral Nonstructural Proteins/genetics , Viral Nonstructural Proteins/metabolism , Virus Replication/drug effectsABSTRACT
A novel unsymmetrical structural class of HCV NS5A inhibitors showing picomolar range antiviral activity has been identified. An unsymmetrical lead compound 2, generated from a substructure of a known symmetrical inhibitor 1, was optimized by extension of its substituents to interact with the hitherto unexplored site of the target protein. This approach afforded novel highly potent unsymmetrical inhibitor 20, which not only equally inhibited HCV genotypes1a, 1b, and 2a with EC50 values in the picomolar range, but also inhibited the 1a Q30K mutant induced by a launched symmetrical inhibitor daclatasvir with an EC50 in the low nanomolar range.
Subject(s)
Antiviral Agents/pharmacology , Glycine/analogs & derivatives , Glycine/pharmacology , Hepacivirus/chemistry , Imidazoles/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Antiviral Agents/chemical synthesis , Cell Line, Tumor , Humans , Imidazoles/chemical synthesis , Microbial Sensitivity Tests , Molecular StructureABSTRACT
Studies on the relationship between the structure of the benzene moiety of S-(2-(acylamino)phenyl) 2,2-dimethylpropanethioates and CETP inhibitory activity were performed. Substituents on the benzene moiety influenced CETP inhibitory activity in a type and position dependent manner, and electron-withdrawing groups at the 4- or 5-position increased the activity. The most potent compound showed 50% inhibition of CETP activity in human plasma at a concentration of 2 microM.
Subject(s)
Carrier Proteins/antagonists & inhibitors , Glycoproteins/antagonists & inhibitors , Sulfhydryl Compounds/pharmacology , Amides , Arteriosclerosis/prevention & control , Carrier Proteins/blood , Cholesterol Ester Transfer Proteins , Cholesterol, HDL/agonists , Esters , Glycoproteins/blood , Humans , Inhibitory Concentration 50 , Protective Agents/chemical synthesis , Protective Agents/pharmacology , Quinolines , Structure-Activity Relationship , Sulfhydryl Compounds/chemical synthesisABSTRACT
A series of 4-aryl/cycloalkyl-5-phenyloxazole derivatives was synthesized and evaluated for their ability to inhibit cyclooxygenase-2 (COX-2) and cyclooxygenase-1 (COX-1). These compounds were found to be potent and selective COX-2 inhibitors.
