Tetracyclic indole inhibitors of hepatitis C virus NS5B-polymerase

Ian Stansfield; Caterina Ercolani; Angela Mackay; Immacolata Conte; Marco Pompei; Uwe Koch; Nadia Gennari; Claudio Giuliano; Michael Rowley; Frank Narjes

doi:10.1016/j.bmcl.2008.12.068

Tetracyclic indole inhibitors of hepatitis C virus NS5B-polymerase

Bioorg Med Chem Lett. 2009 Feb 1;19(3):627-32. doi: 10.1016/j.bmcl.2008.12.068. Epub 2008 Dec 24.

Authors

Ian Stansfield¹, Caterina Ercolani, Angela Mackay, Immacolata Conte, Marco Pompei, Uwe Koch, Nadia Gennari, Claudio Giuliano, Michael Rowley, Frank Narjes

Affiliation

¹ Department of Medicinal Chemistry, Istituto di Ricerche di Biologia Molecolare P. Angeletti S.p.A., Merck Research Laboratories Rome, 00040 Pomezia, Italy. [email protected]

PMID: 19131244
DOI: 10.1016/j.bmcl.2008.12.068

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Allosteric Site
Animals
Chemistry, Pharmaceutical / methods*
Drug Design
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / pharmacology
Hepacivirus
Humans
Hydrolysis
Indoles / chemistry
Models, Chemical
Nitrogen / chemistry
Protein Conformation
Rats
Structure-Activity Relationship
Viral Nonstructural Proteins / antagonists & inhibitors*

Substances

Enzyme Inhibitors
Indoles
Viral Nonstructural Proteins
NS-5 protein, hepatitis C virus
Nitrogen