Finger loop inhibitors of the HCV NS5b polymerase. Part II. Optimization of tetracyclic indole-based macrocycle leading to the discovery of TMC647055
| Autor: | Sandrine Vendeville, Tse-I. Lin, Lili Hu, Abdellah Tahri, David McGowan, Maxwell D. Cummings, Katie Amssoms, Maxime Canard, Stefaan Last, Iris Van den Steen, Benoit Devogelaere, Marie-Claude Rouan, Leen Vijgen, Jan Martin Berke, Pascale Dehertogh, Els Fransen, Erna Cleiren, Liesbet van der Helm, Gregory Fanning, Kristof Van Emelen, Origène Nyanguile, Kenny Simmen, Pierre Raboisson |
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| Rok vydání: | 2012 |
| Předmět: |
Indoles
Macrocyclic Compounds Stereochemistry Hepatitis C virus Clinical Biochemistry Allosteric regulation Drug Evaluation Preclinical Pharmaceutical Science Hepacivirus Viral Nonstructural Proteins Virus Replication Ring (chemistry) medicine.disease_cause Antiviral Agents Heterocyclic Compounds 4 or More Rings Biochemistry Rats Sprague-Dawley Structure-Activity Relationship Allosteric Regulation Pharmacokinetics Cell Line Tumor Drug Discovery medicine Animals Humans Structure–activity relationship Potency Enzyme Inhibitors Molecular Biology Indole test Sulfonamides Chemistry Organic Chemistry Rats Liver Cell culture Molecular Medicine |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 22:4437-4443 |
| ISSN: | 0960-894X |
| Popis: | 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-1 H ,11 H -14,10,2,9,11,17-benzoxathiatetraazacyclo docosine-8,18(9 H ,15 H )-dione, TMC647055 (compound 18a ). This non-zwitterionic 17-membered ring macrocycle combines nanomolar cellular potency (EC 50 of 82 nM) with minimal associated cell toxicity (CC 50 >20 μM) and promising pharmacokinetic profiles in rats and dogs. TMC647055 is currently being evaluated in the clinic. |
| Databáze: | OpenAIRE |
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