ABSTRACT
The HCV RNA-dependent RNA polymerase has emerged as one of the key targets for novel anti-HCV therapy development. Herein, we report the optimization of the dihydropyrone series inhibitors to improve compound aqueous solubility and reduce CYP2D6 inhibition, which led to the discovery of compound 24 (PF-00868554). Compound 24 is a potent and selective HCV polymerase inhibitor with a favorable pharmacokinetic profile and has recently entered a phase II clinical evaluation in patients with genotype 1 HCV.
Subject(s)
Antiviral Agents/chemical synthesis , Hepacivirus/enzymology , Pyrones/chemical synthesis , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Triazoles/chemical synthesis , Administration, Oral , Animals , Antiviral Agents/pharmacokinetics , Antiviral Agents/pharmacology , Crystallography, X-Ray , Cytochrome P-450 CYP2D6 Inhibitors , Dogs , Macaca fascicularis , Microsomes, Liver/metabolism , Models, Molecular , Pyrones/pharmacokinetics , Pyrones/pharmacology , Rats , Rats, Sprague-Dawley , Solubility , Stereoisomerism , Structure-Activity Relationship , Triazoles/pharmacokinetics , Triazoles/pharmacologyABSTRACT
The discovery and optimization of a novel class of carbon-linked dihydropyrones as allosteric HCV NS5B polymerase inhibitors are presented. Replacement of the sulfur linker atom with carbon reduced compound acidity and greatly increased cell permeation. Further structure-activity relationship (SAR) studies led to the identification of compounds, exemplified by 23 and 24, with significantly improved antiviral activities in the cell-based replicon assay and favorable pharmacokinetic profiles.
