Fujiwara T, Sato A, el-Farrash M, Miki S, Abe K, Isaka Y, Kodama M, Wu Y, Chen L B, Harada H, Sugimoto H, Hatanaka M, Hinuma Y
Shionogi Research Laboratories, Shionogi & Co. Ltd., Osaka, Japan.
Antimicrob Agents Chemother. 1998 Jun;42(6):1340-5. doi: 10.1128/AAC.42.6.1340.
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.
S-1153是一种新型咪唑化合物，作为非核苷类逆转录酶抑制剂（NNRTI）抑制1型人类免疫缺陷病毒（HIV-1）复制。该化合物可抑制对核苷类和非核苷类逆转录酶抑制剂耐药的HIV-1毒株的复制。对于具有导致NNRTI耐药的单氨基酸取代的毒株，包括Y181C突变体，S-1153的半数有效浓度在0.3至7 ng/ml范围内，并且对临床分离株也具有强效活性。S-1153耐药变异株的出现比奈韦拉平慢，且S-1153耐药变异株至少包含两个氨基酸取代，包括F227L或L234I。S-1153耐药变异株对核苷类逆转录酶抑制剂齐多夫定（AZT）和拉米夫定仍敏感。在小鼠和MT-4（人T细胞系）体内HIV复制模型中，口服给予S-1153和AZT对HIV-1复制的抑制显示出显著的协同作用。S-1153在淋巴结中有显著蓄积，而大多数HIV-1感染被认为发生在淋巴结中。S-1153可能是HIV感染两药或三药联合治疗的合适候选药物。
