Structure-based design, synthesis, and biological evaluation of 1,1-dioxoisothiazole and benzo[ b]thiophene-1,1-dioxide derivatives as novel inhibitors of hepatitis C virus NS5B polymerase

• Published in: Bioorganic & medicinal chemistry Vol. 18; no. 14; pp. 4181 - 4185
• Main Authors: Kim, Sun Hee, Tran, Martin T., Ruebsam, Frank, Xiang, Alan X., Ayida, Benjamin, McGuire, Helen, Ellis, David, Blazel, Julie, Tran, Chinh V., Murphy, Douglas E., Webber, Stephen E., Zhou, Yuefen, Shah, Amit M., Tsan, Mei, Showalter, Richard E., Patel, Rupal, Gobbi, Alberto, LeBrun, Laurie A., Bartkowski, Darian M., Nolan, Thomas G., Norris, Daniel A., Sergeeva, Maria V., Kirkovsky, Leo, Zhao, Qiang, Han, Qing, Kissinger, Charles R.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 15.07.2008; Elsevier
• Subjects: 1,1-Dioxoisothiazole; 60 APPLIED LIFE SCIENCES; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - chemical synthesis; Antiviral Agents - pharmacokinetics; BASIC BIOLOGICAL SCIENCES; Benzo[ b]thiophene-1,1-dioxide; Biological and medical sciences; CELL CULTURES; Chemistry, Pharmaceutical - methods; Crystallography, X-Ray - methods; DESIGN; DMPK properties; Drug Design; Enzyme Inhibitors - pharmacokinetics; EVALUATION; GENOTYPE; HEPATITIS; Hepatitis C virus; Hepatitis C virus (HCV); Humans; INHIBITION; Inhibitory Concentration 50; Medical sciences; Models, Chemical; Molecular Conformation; NS5B inhibitors; Pharmacology. Drug treatments; POLYMERASES; REPLICONS; RNA, Viral - metabolism; Structure-Activity Relationship; SYNTHESIS; Thiazoles - chemical synthesis; Thiazoles - pharmacokinetics; Thiophenes - chemical synthesis; Thiophenes - pharmacokinetics; Viral Nonstructural Proteins - antagonists & inhibitors; X-ray co-crystal structures; X-ray co-crystal structures; DMPK properties; NS5B inhibitors; Benzo[ b]thiophene-1,1-dioxide; 1,1-Dioxoisothiazole; Hepatitis C virus (HCV); Sulfonamide; Enzyme; Transferases; Lactam; Enzyme inhibitor; In vitro; RNA-directed RNA polymerase; 1,1-Dioxoisothiazole,Benzo[b]thiophene-1,1 -dioxide,Hepatitis C virus (HCV),NS5B inhibitors,X-ray co-crystal structures,DMPK properties; Pyrrole derivatives; Virus; Benzothiophene derivatives; Nucleotidyltransferases; Structure activity relation; Chlorine Organic compounds; Antiviral; Fluorine Organic compounds; Flaviviridae; Pharmacokinetics; Chemical synthesis; Hepatitis C virus; Hepacivirus; Crystalline structure
• ISSN: 0960-894X; 0968-0896; 1464-3405; 1464-3391
• DOI: 10.1016/j.bmcl.2008.05.083

1,1-Dioxoisothiazole and benzo[ b]thiophene-1,1-dioxide analogs were synthesized and tested as HCV NS5B polymerase inhibitors. Their PK properties were also evaluated. A novel series of HCV NS5B polymerase inhibitors comprising 1,1-dioxoisothiazoles and benzo[ b]thiophene-1,1-dioxides were designed, synthesized, and evaluated. SAR studies guided by structure-based design led to the identification of a number of potent NS5B inhibitors with nanomolar IC 50 values. The most potent compound exhibited IC 50 less than 10 nM against the genotype 1b HCV polymerase and EC 50 of 70 nM against a genotype 1b replicon in cell culture. The DMPK properties of selected compounds were also evaluated.