Further studies on hepatitis C virus NS5B RNA-dependent RNA polymerase inhibitors toward improved replicon cell activities: benzimidazole and structurally related compounds bearing the 2-morpholinophenyl moiety.
Following the discovery of JTK-109 (1) as a potent inhibitor of hepatitis C virus NS5B RNA-dependent RNA polymerase, [(a) Hirashima, S.; Suzuki, T.; Ishida, T.; Noji, S.; Yata, S.; Ando, I.; Komatsu, M.; Ikeda, S.; Hashimoto, H. J. Med. Chem.2006, 49, 4721. (b) Hashimoto, H.; Mizutani, K.; Yoshida, A. Int. Patent Appl. WO 01/47883, 2001.] further studies toward the improvement of the cellular potency have been performed. A greater than 40-fold improvement was achieved through replacing the biphenyl moiety with a 2-morpholinophenyl group and the benzimidazole ring with the tetracyclic scaffold to afford compound 7 with an excellent replicon potency (EC(50)=7.6 nM).
Hirashima
Shintaro
S
Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan. hiromasa.hashimoto@ims.jti.co.jp
Oka
Takahiro
T
Ikegashira
Kazutaka
K
Noji
Satoru
S
Yamanaka
Hiroshi
H
Hara
Yoshinori
Y
Goto
Hiroyuki
H
Mizojiri
Ryo
R
Niwa
Yasushi
Y
Noguchi
Toru
T
Ando
Izuru
I
Ikeda
Satoru
S
Hashimoto
Hiromasa
H
D001562:Benzimidazoles / Q000737:chemistry*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D009025:Morpholines / Q000737:chemistry*; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D014779:Virus Replication / Q000187:drug effects; D012324:RNA-Dependent RNA Polymerase
D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D009025:Morpholines; D017361:Viral Nonstructural Proteins; C031000:benzimidazole; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase