Discovery of Conformationally Constrained Tetracyclic Compounds as Potent Hepatitis C Virus NS5B RNA Polymerase Inhibitors

We report a new series of hepatitis C virus NS5B RNA polymerase inhibitors containing a conformationally constrained tetracyclic scaffold. SAR studies led to the identification of 6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indoles (19 and 20) bearing a basic pendent group with high biochemical an...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2006-11, Vol.49 (24), p.6950-6953
Main Authors: Ikegashira, Kazutaka, Oka, Takahiro, Hirashima, Shintaro, Noji, Satoru, Yamanaka, Hiroshi, Hara, Yoshinori, Adachi, Tsuyoshi, Tsuruha, Jun-Ichiro, Doi, Satoki, Hase, Yasunori, Noguchi, Toru, Ando, Izuru, Ogura, Naoki, Ikeda, Satoru, Hashimoto, Hiromasa
Format: Article
Language:English
Subjects:
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antiviral agents
Antiviral Agents - chemical synthesis
Antiviral Agents - chemistry
Antiviral Agents - pharmacology
Benzodiazepines - chemical synthesis
Benzodiazepines - chemistry
Benzodiazepines - pharmacology
Biological and medical sciences
Crystallography, X-Ray
Hepacivirus - enzymology
Hepacivirus - genetics
Hepatitis C virus
Heterocyclic Compounds, 4 or More Rings - chemical synthesis
Heterocyclic Compounds, 4 or More Rings - chemistry
Heterocyclic Compounds, 4 or More Rings - pharmacology
Humans
Indoles - chemical synthesis
Indoles - chemistry
Indoles - pharmacology
Medical sciences
Models, Molecular
Molecular Conformation
Pharmacology. Drug treatments
Replicon
RNA, Viral - genetics
Serum Albumin
Structure-Activity Relationship
Viral Nonstructural Proteins - antagonists & inhibitors
Viral Nonstructural Proteins - chemistry
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Summary:We report a new series of hepatitis C virus NS5B RNA polymerase inhibitors containing a conformationally constrained tetracyclic scaffold. SAR studies led to the identification of 6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indoles (19 and 20) bearing a basic pendent group with high biochemical and cellular potencies. These compounds displayed a very small shift in cellular potency when the replicon assay was performed in the presence of human serum albumin.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm0610245