Tetracyclic indole inhibitors of hepatitis C virus NS5B-polymerase

The evolutionary path is reported to conformationally constrained indole inhibitors of HCV NS5B-polymerase. Biochemical and cell-based potency was achieved, coupled with attractive DMPK properties—leading ultimately to the identification of a pre-clinical candidate with an excellent predicted human...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2009-02, Vol.19 (3), p.627-632
Main Authors: Stansfield, Ian, Ercolani, Caterina, Mackay, Angela, Conte, Immacolata, Pompei, Marco, Koch, Uwe, Gennari, Nadia, Giuliano, Claudio, Rowley, Michael, Narjes, Frank
Format: Article
Language:English
Subjects:
Allosteric inhibitors
Allosteric Site
Animals
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antiviral agents
Biological and medical sciences
Chemistry, Pharmaceutical - methods
Drug Design
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - pharmacology
Hepacivirus
Hepatitis C virus
Humans
Hydrolysis
Indoles - chemistry
Medical sciences
Models, Chemical
Nitrogen - chemistry
NS5B-polymerase
Pharmacology. Drug treatments
Pre-clinical candidate
Protein Conformation
Rats
Structure-Activity Relationship
Tetracyclic indoles
Viral Nonstructural Proteins - antagonists & inhibitors
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Summary:The evolutionary path is reported to conformationally constrained indole inhibitors of HCV NS5B-polymerase. Biochemical and cell-based potency was achieved, coupled with attractive DMPK properties—leading ultimately to the identification of a pre-clinical candidate with an excellent predicted human pharmacokinetic profile. We report the evolutionary path from an open-chain series to conformationally constrained tetracyclic indole inhibitors of HCV NS5B-polymerase, where the C2 aromatic is tethered to the indole nitrogen. SAR studies led to the discovery of zwitterionic compounds endowed with good intrinsic enzyme affinity and cell-based potency, as well as superior DMPK profiles to their acyclic counterparts, and ultimately to the identification of a pre-clinical candidate with an excellent predicted human pharmacokinetic profile.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2008.12.068