title: Discovery of conformationally constrained tetracyclic compounds as potent hepatitis C virus NS5B RNA polymerase inhibitors.
abstract: 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.
authors.affiliation: Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan. kazutaka.ikegashira@ims.jti.co.jp
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Ikegashira
authors.forename: Takahiro
authors.initials: T
authors.lastname: Oka
authors.forename: Shintaro
authors.initials: S
authors.lastname: Hirashima
authors.forename: Satoru
authors.initials: S
authors.lastname: Noji
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamanaka
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Hara
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Adachi
authors.forename: Jun-Ichiro
authors.initials: J
authors.lastname: Tsuruha
authors.forename: Satoki
authors.initials: S
authors.lastname: Doi
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Hase
authors.forename: Toru
authors.initials: T
authors.lastname: Noguchi
authors.forename: Izuru
authors.initials: I
authors.lastname: Ando
authors.forename: Naoki
authors.initials: N
authors.lastname: Ogura
authors.forename: Satoru
authors.initials: S
authors.lastname: Ikeda
authors.forename: Hiromasa
authors.initials: H
authors.lastname: Hashimoto
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D016174:Hepacivirus / Q000201:enzymology* / Q000235:genetics; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D008968:Molecular Conformation; D012367:RNA, Viral / Q000235:genetics; D012093:Replicon; D012709:Serum Albumin; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D001569:Benzodiazepines; D006576:Heterocyclic Compounds, 4 or More Rings; D007211:Indoles; D012367:RNA, Viral; D012709:Serum Albumin; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase