title: YM-53403, a unique anti-respiratory syncytial virus agent with a novel mechanism of action.
abstract: We performed a large-scale random screening of an in-house chemical library based on the inhibition of respiratory syncytial virus (RSV)-induced cytopathic effect on HeLa (human cervical carcinoma) cells, and found a novel and specific anti-RSV agent, 6-{4-[(biphenyl-2-ylcarbonyl) amino]benzoyl}-N-cyclopropyl-5,6-dihydro-4H-thieno[3,2-d][1]benzazepine-2-carboxamide (YM-53403). YM-53403 potently inhibited the replication of RSV strains belonging to both A and B subgroups, but not influenza A virus, measles virus, or herpes simplex virus type 1. A plaque reduction assay was used to determine the 50% effective concentration (EC(50)) value for YM-53403. The value, 0.20 microM, was about 100-fold more potent than ribavirin. The result of a time-dependent drug addition test showed that YM-53403 inhibited the life cycle of RSV at around 8h post-infection, suggesting an inhibitory effect on early transcription and/or replication of the RSV genome. Consistent with this result, two YM-53403-resistant viruses have a single point mutation (Y1631H) in the L protein which is a RNA polymerase for both the transcription and replication of the RSV genome. YM-53403 is an attractive compound for the treatment of RSV infection because of its highly potent anti-RSV activity and the new mode of action, which differs from that of currently reported antiviral agents.
authors.affiliation: Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co. Ltd., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. sudou.kenji@yamanouchi.co.jp
authors.forename: Kenji
authors.initials: K
authors.lastname: Sudo
authors.forename: Yoji
authors.initials: Y
authors.lastname: Miyazaki
authors.forename: Naoko
authors.initials: N
authors.lastname: Kojima
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suzuki
authors.forename: Masafumi
authors.initials: M
authors.lastname: Shintani
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Shimizu
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D001552:Benzazepines / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D002522:Chlorocebus aethiops; D003521:Cyclopropanes / Q000737:chemistry / Q000494:pharmacology*; D004285:Dogs; D024882:Drug Resistance, Viral / Q000235:genetics; D005814:Genes, Viral; D006367:HeLa Cells; D006801:Humans; D008826:Microbial Sensitivity Tests; D017354:Point Mutation; D012136:Respiratory Syncytial Viruses / Q000187:drug effects* / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology; D014709:Vero Cells; D014764:Viral Proteins / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects
chemical_list: C500207:6-(4-((biphenyl-2-ylcarbonyl) amino)benzoyl)1-N-cyclopropyl-5,6-dihydro-4H-thieno(3,2-d)(1)benzazepine-2-carboxamide; D000998:Antiviral Agents; D001552:Benzazepines; D003521:Cyclopropanes; D014764:Viral Proteins