ABSTRACT
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
A matched and mixed capping SAR study was conducted on the tetracyclic indole class of HCV NS5A inhibitors to examine the influence of modifications of this region on the overall HCV virologic resistance profiles.
Subject(s)
Antiviral Agents/chemistry , Hepacivirus/metabolism , Indoles/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Area Under Curve , Genotype , Half-Life , Hepacivirus/drug effects , Hepacivirus/genetics , Indoles/metabolism , Indoles/pharmacology , ROC Curve , Rats , Structure-Activity Relationship , Viral Nonstructural Proteins/metabolismABSTRACT
The synthesis and hit-to-lead SAR development of a pyrazolo[1,5-a]pyrimidine hit 4 is described leading to a series of potent, selective CHK1 inhibitors such as compound 17r. In the Letter, the further utility of the pyrazolo[1,5-a]pyrimidine template for the development of potent, selective kinase inhibitors is detailed.
