Ferris Robert G, Hazen Richard J, Roberts Grace B, St Clair Marty H, Chan Joseph H, Romines Karen R, Freeman George A, Tidwell Jeffrey H, Schaller Lee T, Cowan Jill R, Short Steven A, Weaver Kurt L, Selleseth Dean W, Moniri Kelly R, Boone Lawrence R
Department of Virology, GlaxoSmithKline, Research Triangle Park, NC 27709, USA.
Antimicrob Agents Chemother. 2005 Oct;49(10):4046-51. doi: 10.1128/AAC.49.10.4046-4051.2005.
The compound GW678248 is a novel benzophenone nonnucleoside reverse transcriptase inhibitor (NNRTI). Preclinical assessment of GW678248 indicates that this compound potently inhibits wild-type (WT) and mutant human immunodeficiency virus type 1 (HIV-1) reverse transcriptase in biochemical assays, with 50% inhibitory concentrations (IC(50)s) between 0.8 and 6.8 nM. In HeLa CD4 MAGI cell culture virus replication assays, GW678248 has an IC(50) of < or =21 nM against HIV-1 isogenic strains with single or double mutations known to be associated with NNRTI resistance, including L100I, K101E, K103N, V106A/I/M, V108I, E138K, Y181C, Y188C, Y188L, G190A/E, P225H, and P236L and various combinations. An IC(50) of 86 nM was obtained with a mutant virus having V106I, E138K, and P236L mutations that resulted from serial passage of WT virus in the presence of GW678248. The presence of 45 mg/ml human serum albumin plus 1 mg/ml alpha-1 acid glycoprotein increased the IC(50) approximately sevenfold. Cytotoxicity studies with GW678248 indicate that the 50% cytotoxicity concentration is greater than the level of compound solubility and provides a selectivity index of >2,500-fold for WT, Y181C, or K103N HIV-1. This compound exhibits excellent preclinical antiviral properties and, as a prodrug designated GW695634, is being developed as a new generation of NNRTI for the treatment of HIV-1 in combination with other antiretroviral agents.
化合物GW678248是一种新型二苯甲酮非核苷类逆转录酶抑制剂（NNRTI）。GW678248的临床前评估表明，该化合物在生化试验中能有效抑制野生型（WT）和突变型人类免疫缺陷病毒1型（HIV-1）逆转录酶，50%抑制浓度（IC50）在0.8至6.8 nM之间。在HeLa CD4 MAGI细胞培养病毒复制试验中，GW678248对已知与NNRTI耐药相关的单突变或双突变HIV-1同基因株的IC50≤21 nM，这些突变包括L100I、K101E、K103N、V106A/I/M、V108I、E138K、Y181C、Y188C、Y188L、G190A/E、P225H和P236L以及各种组合。对于在GW678248存在下经野生型病毒连续传代产生的具有V106I、E138K和P236L突变的突变病毒，其IC50为86 nM。45 mg/ml人血清白蛋白加1 mg/mlα-1酸性糖蛋白的存在使IC50增加约7倍。GW678248的细胞毒性研究表明，50%细胞毒性浓度大于化合物溶解度水平，对野生型、Y181C或K103N HIV-1的选择性指数>2500倍。该化合物具有出色的临床前抗病毒特性，作为前体药物GW695634，正被开发为新一代NNRTI，与其他抗逆转录病毒药物联合用于治疗HIV-1。
