Allosteric Inhibitors of Hepatitis C Polymerase:  Discovery of Potent and Orally Bioavailable Carbon-Linked Dihydropyrones

• Published in: Journal of medicinal chemistry Vol. 50; no. 17; pp. 3969 - 3972
• Main Authors: Li, Hui, Linton, Angelica, Tatlock, John, Gonzalez, Javier, Borchardt, Allen, Abreo, Mel, Jewell, Tanya, Patel, Leena, Drowns, Matthew, Ludlum, Sarah, Goble, Mike, Yang, Michele, Blazel, Julie, Rahavendran, Ravi, Skor, Heather, Shi, Stephanie, Lewis, Cristina, Fuhrman, Shella
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 23.08.2007; Amer Chemical Soc
• Subjects: Administration, Oral; Allosteric Regulation; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Biological and medical sciences; Biological Availability; Caco-2 Cells; Cell Line, Tumor; Chemistry, Medicinal; Half-Life; Hepacivirus - enzymology; Hepatitis C virus; Humans; Life Sciences & Biomedicine; Medical sciences; Permeability; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Pyrones - chemical synthesis; Pyrones - chemistry; Pyrones - pharmacology; Rats; Science & Technology; Stereoisomerism; Structure-Activity Relationship; Viral Nonstructural Proteins - antagonists & inhibitors; Viral Nonstructural Proteins - genetics; THERAPEUTICS; IDENTIFICATION; Nitrile; Rat; Angular nitrogen heterocycle; Oxygen heterocycle; Six membered ring; Enantiomer; Bicyclic compound; Antiviral; Enzyme; Transferases; Rodentia; Benzene derivatives; Oral administration; Enzyme inhibitor; Lactone; Bioavailability; Pyranone derivatives; In vitro; RNA-directed RNA polymerase; Virus; In vivo; Allosteric inhibitor; Nucleotidyltransferases; Vertebrata; Mammalia; Animal; Fluorine Organic compounds; Flaviviridae; Hepatitis C virus; Hepacivirus; Cyclopentane derivatives
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0704447

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.