Discovery of pentacyclic compounds as potent inhibitors of hepatitis C virus NS5B RNA polymerase

Jörg Habermann; Elena Capitò; Maria del Rosario Rico Ferreira; Uwe Koch; Frank Narjes

doi:10.1016/j.bmcl.2008.12.039

Discovery of pentacyclic compounds as potent inhibitors of hepatitis C virus NS5B RNA polymerase

Bioorg Med Chem Lett. 2009 Feb 1;19(3):633-8. doi: 10.1016/j.bmcl.2008.12.039. Epub 2008 Dec 13.

Authors

Jörg Habermann¹, Elena Capitò, Maria del Rosario Rico Ferreira, Uwe Koch, Frank Narjes

Affiliation

¹ Department of Medicinal Chemistry, IRBM P. Angeletti S.p.A., Merck Research Laboratories Rome, Via Pontina km 30,600, I-00040 Pomezia, Rome, Italy. jorg_habermann@merck.com

PMID: 19109015
DOI: 10.1016/j.bmcl.2008.12.039

Abstract

We report a new series of inhibitors for hepatitis C virus NS5B RNA polymerase containing a constrained pentacyclic scaffold. Our SAR studies led to the identification of hexahydroindolo[2,1-a]pyrrolo[3,2-d][2]benzazepines exposing basic groups. The compounds displayed a high activity in the enzyme assay and displayed good activity in the cell-based (replicon) assay in the presence of serum proteins.

MeSH terms

Benzazepines / chemistry
Chemistry, Pharmaceutical / methods*
DNA-Directed RNA Polymerases / chemistry
Drug Design*
Enzyme Inhibitors / pharmacology
Humans
Inhibitory Concentration 50
Liver / drug effects
Liver / virology
Models, Chemical
Models, Molecular
Molecular Conformation
RNA, Viral / genetics
Structure-Activity Relationship
Viral Nonstructural Proteins / antagonists & inhibitors*
Viral Nonstructural Proteins / chemistry*

Substances

Benzazepines
Enzyme Inhibitors
RNA, Viral
Viral Nonstructural Proteins
NS-5 protein, hepatitis C virus
DNA-Directed RNA Polymerases