ABSTRACT
We describe the discovery of MK-6169, a potent and pan-genotype hepatitis C virus NS5A inhibitor with optimized activity against common resistance-associated substitutions. SAR studies around the combination of changes to both the valine and aminal carbon region of elbasvir led to the discovery of a series of compounds with substantially improved potency against common resistance-associated substitutions in the major genotypes, as well as good pharmacokinetics in both rat and dog. Through further optimization of key leads from this effort, MK-6169 (21) was discovered as a preclinical candidate for further development.
Subject(s)
Antiviral Agents/pharmacology , Drug Discovery , Drug Resistance, Viral/drug effects , Hepacivirus/drug effects , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/pharmacokinetics , Dogs , Genotype , Hepacivirus/genetics , Hepacivirus/metabolism , Male , Rats , Tissue DistributionABSTRACT
We describe the research that led to the discovery of compound 40 (ruzasvir, MK-8408), a pan-genotypic HCV nonstructural protein 5A (NS5A) inhibitor with a "flat" GT1 mutant profile. This NS5A inhibitor contains a unique tetracyclic indole core while maintaining the imidazole-proline-valine Moc motifs of our previous NS5A inhibitors. Compound 40 is currently in early clinical trials and is under evaluation as part of an all-oral DAA regimen for the treatment of chronic HCV infection.
Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Hepacivirus/drug effects , Heterocyclic Compounds, 4 or More Rings/chemistry , Heterocyclic Compounds, 4 or More Rings/pharmacology , Polymorphism, Genetic , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Thiazoles/chemistry , Thiazoles/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/pharmacokinetics , Cell Line , Dogs , Haplorhini , Hepacivirus/genetics , Heterocyclic Compounds, 4 or More Rings/pharmacokinetics , Humans , Pyrrolidines/pharmacokinetics , Rats , Structure-Activity Relationship , Thiazoles/pharmacokineticsABSTRACT
The discovery of potent and pan-genotypic HCV NS5A inhibitors faces many challenges including the significant diversity among genotypes, substantial potency shift conferred on some key resistance-associated variants, inconsistent SARs between different genotypes and mutants, and the lacking of models of inhibitor/protein complexes for rational inhibitor design. As part of ongoing efforts on HCV NS5A inhibition at Merck, we now describe the discovery of a novel series of chromane containing NS5A inhibitors. SAR studies around the "Z" group of the tetracyclic indole scaffold explored fused bicyclic rings as alternates to the phenyl group of elbasvir (1, MK-8742) and identified novel chromane and 2,3-dihydrobenzofuran derivatives as "Z" group replacements offered good potency across all genotypes. This effort, incorporating the C-1 fluoro substitution at the tetracyclic indole core, led to the discovery of a new series of NS5A inhibitors, such as compounds 14 and 25-28, with significantly improved potency against resistance-associated variants, such as GT2b, GT1a Y93H, and GT1a L31V. Compound 14 also showed reasonable PK exposures in preclinical species (rat and dog).
Subject(s)
Antiviral Agents/pharmacology , Chromans/pharmacology , Drug Discovery , Drug Resistance, Viral/drug effects , Hepacivirus/drug effects , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Chromans/chemical synthesis , Chromans/chemistry , Dogs , Dose-Response Relationship, Drug , Male , Microbial Sensitivity Tests , Molecular Structure , Rats , Rats, Wistar , Structure-Activity RelationshipABSTRACT
We describe the impact of proline modifications, in our tetracyclic-indole based series of nonstructural protein 5A (NS5A) inhibitors, to their replicon profiles. This work identified NS5A inhibitors with an improved and flattened resistance profiles.
Subject(s)
Antiviral Agents/pharmacology , Benzofurans/pharmacology , Imidazoles/pharmacology , Indoles/chemistry , Proline/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Antiviral Agents/chemistry , Benzofurans/chemistry , Imidazoles/chemistry , Structure-Activity RelationshipABSTRACT
As part of an ongoing effort in NS5A inhibition at Merck we now describe our efforts for introducing substitution around the tetracyclic indole core of MK-8742. Fluoro substitution on the core combined with the fluoro substitutions on the proline ring improved the potency against GT1a Y93H significantly. However, no improvement on GT2b potency was achieved. Limiting the fluoro substitution to C-1 of the tetracyclic indole core had a positive impact on the potency against the resistance associated variants, such as GT1a Y93H and GT2b, and the PK profile as well. Compounds, such as 62, with reduced potency shifts between wild type GT1a to GT2b, GT1a Y93H, and GT1a L31V were identified.
Subject(s)
Antiviral Agents/pharmacology , Benzofurans/pharmacology , Imidazoles/pharmacology , Indoles/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Benzofurans/chemistry , Benzofurans/pharmacokinetics , Imidazoles/chemistry , Imidazoles/pharmacokinetics , Indoles/chemistry , Indoles/pharmacokinetics , Structure-Activity RelationshipABSTRACT
Herein we describe our research efforts around the aryl and heteroaryl substitutions at the aminal carbon of the tetracyclic indole-based HCV NS5A inhibitor MK-8742. A series of potent NS5A inhibitors are described, such as compounds 45-47, 54, 56, and 65, which showed improved potency against clinically relevant and resistance associated HCV variants. The improved potency profiles of these compounds demonstrated an SAR that can improve the potency against GT2b, GT1a Y93H, and GT1a L31V altogether, which was unprecedented in our previous efforts in NS5A inhibition.
