Finger loop inhibitors of the HCV NS5b polymerase. Part II. Optimization of tetracyclic indole-based macrocycle leading to the discovery of TMC647055

• Published in: Bioorganic & medicinal chemistry letters Vol. 22; no. 13; pp. 4437 - 4443
• Main Authors: Vendeville, Sandrine, Lin, Tse-I., Hu, Lili, Tahri, Abdellah, McGowan, David, Cummings, Maxwell D., Amssoms, Katie, Canard, Maxime, Last, Stefaan, Van den Steen, Iris, Devogelaere, Benoit, Rouan, Marie-Claude, Vijgen, Leen, Berke, Jan Martin, Dehertogh, Pascale, Fransen, Els, Cleiren, Erna, van der Helm, Liesbet, Fanning, Gregory, Van Emelen, Kristof, Nyanguile, Origène, Simmen, Kenny, Raboisson, Pierre
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.07.2012; Elsevier
• Subjects: Allosteric inhibitor; Allosteric Regulation; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacokinetics; Biological and medical sciences; Cell Line, Tumor; chemistry; dogs; Drug Evaluation, Preclinical; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacokinetics; Finger; Hepacivirus - enzymology; Hepatitis C virus; Heterocyclic Compounds, 4 or More Rings - chemical synthesis; Heterocyclic Compounds, 4 or More Rings - chemistry; Heterocyclic Compounds, 4 or More Rings - pharmacokinetics; Humans; Indoles - chemistry; Liver - metabolism; Macrocycle; Macrocyclic Compounds - chemical synthesis; Macrocyclic Compounds - chemistry; Macrocyclic Compounds - pharmacokinetics; Medical sciences; NS5b polymerase; Pharmacokinetics; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; RNA-directed RNA polymerase; Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Sulfonamides - pharmacokinetics; Toxicity; Viral Nonstructural Proteins - antagonists & inhibitors; Viral Nonstructural Proteins - metabolism; Virus Replication - drug effects; Allosteric inhibitor; Hepatitis C virus; NS5b polymerase; Macrocycle; Enzyme; Transferases; Tetracyclic compound; Optimization; RNA-directed RNA polymerase; Virus; Nucleotidyltransferases; Antiviral; Flaviviridae; Indole derivatives; Hepacivirus
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.04.113

Lead optimization performed on a series of tetracyclic indole-based macrocyclic inhibitors of the HCV NS5b polymerase led to the discovery of TMC647055 (18a), currently in phase 2 clinical trials. Optimization of a novel series of macrocyclic indole-based inhibitors of the HCV NS5b polymerase targeting the finger loop domain led to the discovery of lead compounds exhibiting improved potency in cellular assays and superior pharmacokinetic profile. Further lead optimization performed on the most promising unsaturated-bridged subseries provided the clinical candidate 27-cyclohexyl-12,13,16,17-tetrahydro-22-methoxy-11,17-dimethyl-10,10-dioxide-2,19-methano-3,7:4,1-dimetheno-1H,11H-14,10,2,9,11,17-benzoxathiatetraazacyclo docosine-8,18(9H,15H)-dione, TMC647055 (compound 18a). This non-zwitterionic 17-membered ring macrocycle combines nanomolar cellular potency (EC50 of 82nM) with minimal associated cell toxicity (CC50>20μM) and promising pharmacokinetic profiles in rats and dogs. TMC647055 is currently being evaluated in the clinic.