Discovery of benzimidazole-diamide finger loop (Thumb Pocket I) allosteric inhibitors of HCV NS5B polymerase: Implementing parallel synthesis for rapid linker optimization

• Published in: Bioorganic & medicinal chemistry letters Vol. 20; no. 1; pp. 196 - 200
• Main Authors: Goulet, Sylvie, Poupart, Marc-André, Gillard, James, Poirier, Martin, Kukolj, George, Beaulieu, Pierre L.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 2010; Elsevier
• Subjects: Allosteric inhibitors; Allosteric Regulation; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Benzimidazoles - chemistry; Biological and medical sciences; Cinnamates - chemistry; Diamide - chemical synthesis; Diamide - chemistry; Diamide - pharmacology; Drug Discovery; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; HCV; Hepatitis C virus; Humans; Inhibition; Medical sciences; Microsomes, Liver - metabolism; NS5B polymerase; Pharmacology. Drug treatments; Protein Structure, Tertiary; Replication; Replicon; Structure-Activity Relationship; Viral Nonstructural Proteins - antagonists & inhibitors; Viral Nonstructural Proteins - metabolism; Allosteric inhibitors; Replication; HCV; NS5B polymerase; Inhibition; Hepatitis C virus; Replicon; Cyclohexane derivatives; Spacer arm; Furan derivatives; Combinatorial chemistry; Structure activity relation; Carboxylic acid; Antiviral; Chemical synthesis; Molecular rigidity; Enzyme; Aminoamide; Transferases; Enzyme inhibitor; Virus replication cycle; Steric hindrance; In vitro; RNA-directed RNA polymerase; Virus; Allosteric inhibitor; α-Aminoacid; Nucleotidyltransferases; Benzimidazole derivatives; Carboxamide; Flaviviridae; Hepacivirus; Absorption Distribution Metabolisme Excretion Toxicity
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.10.136

Previously described SAR of benzimidazole-based non-nucleoside finger loop (Thumb Pocket I) inhibitors of HCV NS5B polymerase was expanded. Prospecting studies using parallel synthesis techniques allowed the rapid identification of novel cinnamic acid right-hand sides that provide renewed opportunities for further optimization of these inhibitors. Novel diamide derivatives such as 44 exhibited comparable potency (enzymatic and cell-based HCV replicon) as previously described tryptophan-based inhibitors but physicochemical properties (e.g., aqueous solubility and lipophilicity) have been improved, resulting in molecules with reduced off-target liabilities (CYP inhibition) and increased metabolic stability.