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 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.
Ikegashira
Kazutaka
K
Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan. kazutaka.ikegashira@ims.jti.co.jp
Oka
Takahiro
T
Hirashima
Shintaro
S
Noji
Satoru
S
Yamanaka
Hiroshi
H
Hara
Yoshinori
Y
Adachi
Tsuyoshi
T
Tsuruha
Jun-Ichiro
J
Doi
Satoki
S
Hase
Yasunori
Y
Noguchi
Toru
T
Ando
Izuru
I
Ogura
Naoki
N
Ikeda
Satoru
S
Hashimoto
Hiromasa
H
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
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