TMC125, a novel next-generation nonnucleoside reverse transcriptase inhibitor active against nonnucleoside reverse transcriptase inhibitor-resistant human immunodeficiency virus type 1
TMC125, a novel next-generation nonnucleoside reverse transcriptase inhibitor active against nonnucleoside reverse transcriptase inhibitor-resistant human immunodeficiency virus type 1
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DOI：
10.1128/aac.48.12.4680-4686.2004
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发表时间：
2004-12-01
影响因子：
4.9
通讯作者：
de Béthune, MP
中科院分区：
文献类型：
--
作者：
Andries, K;Azijn, H;de Béthune, MP
非核苷类逆转录酶抑制剂（NNRTI）是人类免疫缺陷病毒1型（HIV-1）的强效抑制剂;然而，目前上市的NNRTI可快速选择耐药病毒，且该类药物的交叉耐药性广泛。应用平行筛选策略来测试来自一系列二芳基嘧啶类药物的候选药物对携带临床相关突变的野生型和耐药HIV毒株的作用。血清蛋白结合和代谢稳定性在选择过程的早期就得到了解决。新兴的临床候选药物TMC 125对野生型HIV-1具有高度活性（50%有效浓度[EC 50] = 1.4至4.8 nM），并显示出一定的抗HIV-2活性（EC 50 = 3.5 μ M）。TMC 125还抑制一系列HIV-1 M组亚型和循环重组形式以及0组病毒。将TMC 125与人肝微粒体组分孵育表明具有良好的代谢稳定性（120 min后药物浓度降低15%，抗病毒活性降低7%）。尽管TMC 125是高度蛋白结合的，但其抗病毒作用不因存在45 mg人血清白蛋白/ml、1 mg α（1）-酸性糖蛋白/ml或50%人血清而降低。在针对一组25种携带与NNRTI抗性相关的单和双逆转录酶氨基酸取代的病毒的活性的初始筛选中，
Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are potent inhibitors of human immunodeficiency virus type 1 (HIV-1); however, currently marketed NNRTIs rapidly select resistant virus, and cross-resistance within the class is extensive. A parallel screening strategy was applied to test candidates from a series of diarylpyrimidines against wild-type and resistant HIV strains carrying clinically relevant mutations. Serum protein binding and metabolic stability were addressed early in the selection process. The emerging clinical candidate, TMC125, was highly active against wild-type HIV-1 (50% effective concentration [EC50] = 1.4 to 4.8 nM) and showed some activity against HIV-2 (EC50 = 3.5 muM). TMC125 also inhibited a series of HIV-1 group M subtypes and circulating recombinant forms and a group 0 virus. Incubation of TMC125 with human liver microsomal fractions suggested good metabolic stability (15% decrease in drug concentration and 7% decrease in antiviral activity after 120 min). Although TMC125 is highly protein bound, its antiviral effect was not reduced by the presence of 45 mg of human serum albumin/ml, 1 mg of alpha(1)-acid glycoprotein/ml, or 50% human serum. In an initial screen for activity against a panel of 25 viruses carrying single and double reverse transcriptase amino acid substitutions associated with NNRTI resistance, the EC50 of TMC125 was