title: S-1153 inhibits replication of known drug-resistant strains of human immunodeficiency virus type 1.
abstract: S-1153 is a new imidazole compound that inhibits human immunodeficiency virus (HIV) type 1 (HIV-1) replication by acting as a nonnucleoside reverse transcriptase inhibitor (NNRTI). This compound inhibits replication of HIV-1 strains that are resistant to nucleoside and nonnucleoside reverse transcriptase inhibitors. S-1153 has a 50% effective concentration in the range of 0.3 to 7 ng/ml for strains with single amino acid substitutions that cause NNRTI resistance, including the Y181C mutant, and also has potent activity against clinical isolates. The emergence of S-1153-resistant variants is slower than that for nevirapine, and S-1153-resistant variants contained at least two amino acid substitutions, including F227L or L234I. S-1153-resistant variants are still sensitive to the nucleoside reverse transcriptase inhibitors zidovudine (AZT) and lamivudine. In a mouse and MT-4 (human T-cell line) in vivo HIV replication model, S-1153 and AZT administered orally showed a marked synergy for the inhibition of HIV-1 replication. S-1153 shows a significant accumulation in lymph nodes, where most HIV-1 infection is thought to occur. S-1153 may be an appropriate candidate for two-to three-drug combination therapy for HIV infection.
authors.affiliation: Shionogi Research Laboratories, Shionogi & Co. Ltd., Osaka, Japan. tamio.fujiwara@shionogi.co.jp
authors.forename: T
authors.initials: T
authors.lastname: Fujiwara
authors.forename: A
authors.initials: A
authors.lastname: Sato
authors.forename: M
authors.initials: M
authors.lastname: el-Farrash
authors.forename: S
authors.initials: S
authors.lastname: Miki
authors.forename: K
authors.initials: K
authors.lastname: Abe
authors.forename: Y
authors.initials: Y
authors.lastname: Isaka
authors.forename: M
authors.initials: M
authors.lastname: Kodama
authors.forename: Y
authors.initials: Y
authors.lastname: Wu
authors.forename: L B
authors.initials: LB
authors.lastname: Chen
authors.forename: H
authors.initials: H
authors.lastname: Harada
authors.forename: H
authors.initials: H
authors.lastname: Sugimoto
authors.forename: M
authors.initials: M
authors.lastname: Hatanaka
authors.forename: Y
authors.initials: Y
authors.lastname: Hinuma
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002478:Cells, Cultured; D004352:Drug Resistance, Microbial; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D013601:T-Lymphocytes; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D019380:Anti-HIV Agents; D007093:Imidazoles; C113604:S 1153