Benzimidazole Thumb Pocket I finger-loop inhibitors of HCV NS5B polymerase: Improved drug-like properties through C-2 SAR in three sub-series

• Published in: Bioorganic & medicinal chemistry letters Vol. 20; no. 6; pp. 1825 - 1829
• Main Authors: Beaulieu, Pierre L., Dansereau, Nathalie, Duan, Jianmin, Garneau, Michel, Gillard, James, McKercher, Ginette, LaPlante, Steven, Lagacée, Lisette, Thauvette, Louise, Kukolj, George
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.03.2010; Elsevier
• Subjects: Administration, Oral; Allosteric inhibitors; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antivirals; Benzimidazole; Benzimidazoles - blood; Benzimidazoles - chemistry; Benzimidazoles - pharmacology; Biological and medical sciences; Enzyme Inhibitors - blood; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; HCV; Hepatitis C virus; Humans; Medical sciences; NS5B polymerase; Pharmacology. Drug treatments; Rats; Replicon inhibitors; Structure-Activity Relationship; Viral Nonstructural Proteins - antagonists & inhibitors; Replicon inhibitors; Benzimidazole; Antivirals; Allosteric inhibitors; HCV; NS5B polymerase; Hepatitis C virus; Cyclohexane derivatives; Rat; Furan derivatives; Pyridine derivatives; Structure activity relation; Carboxylic acid; Antiviral; Chemical synthesis; Unspecific monooxygenase; Absorption Distribution Metabolisme Excretion; Enzyme; Aminoamide; Transferases; Cytochrome P450; Rodentia; Oral administration; Enzyme inhibitor; In vitro; RNA-directed RNA polymerase; Virus; In vivo; Allosteric inhibitor; Nucleotidyltransferases; Vertebrata; Metabolic stability; Mammalia; Benzimidazole derivatives; Animal; Cinnamic acid derivatives; Drug-metabolizing enzyme; Oxidoreductases; Flaviviridae; Pharmacokinetics; Hepacivirus; Cyclopentane derivatives; Lipophilicity; Physicochemical properties; Replicon
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.02.003

SAR at the C-2 position of benzimidazole-based Thumb Pocket I inhibitors of HCV NS5B polymerase revealed parallel activity for distinct sub-series that harbor 5-hydroxytryptophan amides, neutral thiazole isosteres or recently disclosed cinnamic acid diamides. The consistent SAR among the three sub-series suggest a common binding mode to the Thumb Pocket I allosteric site. New inhibitors with sub-micromolar cell-based replicon potency and improved ‘drug-like’ features are disclosed along with preliminary characterization of their ADME-PK profile.