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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Veröffentlicht in:	Journal of medicinal chemistry 2006-11, Vol.49 (24), p.6950-6953
Hauptverfasser:	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:	Artikel
Sprache:	eng
Schlagworte:	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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Beschreibung
Zusammenfassung:	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