Buckheit R W, Snow M J, Fliakas-Boltz V, Kinjerski T L, Russell J D, Pallansch L A, Brouwer W G, Yang S S
Virology Research Group, Southern Research Institute-Frederick Research Center, Maryland 21701, USA.
Antimicrob Agents Chemother. 1997 Apr;41(4):831-7. doi: 10.1128/AAC.41.4.831.
The structure-activity relationships of a series of compounds related to the nonnucleoside reverse transcriptase (RT) inhibitor (NNRTI) oxathiin carboxanilide have been described (R. W. Buckheit, Jr., T. L. Kinjerski, V. Fliakas-Boltz, J. D. Russell, T. L. Stup, L. A. Pallansch, W. G. Brouwer, D. C. Dao, W. A. Harrison, R. J. Schultz, J. P. Bader, and S. S. Yang, Antimicrob. Agents Chemother. 39:2718-2727, 1996). From these studies, the furanyl-containing analog UC10 was identified as the most potent inhibitor of human immunodeficiency virus type 1 (HIV-1) replication and a promising candidate for further development. Three new UC analogs (UC040, UC82, and UC781) have been determined to inhibit laboratory-derived and low-passage-number, primary virus isolates at low nanomolar concentrations in both established and fresh human cells. Each of the compounds synergistically interacted with the nucleoside analogs zidovudine, dideoxyinosine, dideoxycytosine, and lamivudine to inhibit HIV-1 replication. As a group, the UC compounds were found to be less active against viruses with the L100I, K103N, and Y181C amino acid changes in the RT and, upon in vitro selection, yielded resistant virus with the Y181C mutation in the RT. The most potent of the three new compounds, UC781, contains a furanyl side chain, similar to UC10, but differs in having an extended ether side chain instead of an oxime chain. The broad therapeutic index of UC781 (>62,000) resulted in effective inhibition of NNRTI-resistant virus isolates at high nanomolar concentrations. Furthermore, UC781 and the NNRTI costatolide were able to synergistically inhibit HIV-1 replication when used in combination, suggesting that UC781 may interact with the RT differently than the other UC analogs. The favorable anti-HIV properties of the UC compounds suggest they should be considered for further clinical development.
已描述了一系列与非核苷逆转录酶（RT）抑制剂氧硫杂环丁烷甲酰苯胺相关的化合物的构效关系（R. W. Buckheit, Jr., T. L. Kinjerski, V. Fliakas-Boltz, J. D. Russell, T. L. Stup, L. A. Pallansch, W. G. Brouwer, D. C. Dao, W. A. Harrison, R. J. Schultz, J. P. Bader, and S. S. Yang, Antimicrob. Agents Chemother. 39:2718 - 2727, 1996）。通过这些研究，含呋喃基的类似物UC10被确定为人类免疫缺陷病毒1型（HIV - 1）复制的最有效抑制剂，是进一步开发的有前景的候选药物。已确定三种新的UC类似物（UC040、UC82和UC781）在低纳摩尔浓度下可抑制实验室衍生的和低传代次数的原代病毒分离株在已建立的和新鲜的人类细胞中的复制。每种化合物都与核苷类似物齐多夫定、双脱氧肌苷、双脱氧胞苷和拉米夫定协同相互作用以抑制HIV - 1复制。总体而言，发现UC化合物对RT中具有L100I、K103N和Y181C氨基酸变化的病毒活性较低，并且在体外选择时，产生了RT中具有Y181C突变的耐药病毒。三种新化合物中最有效的UC781含有一个呋喃基侧链，与UC10类似，但不同之处在于具有一个延长的醚侧链而不是肟链。UC781的广泛治疗指数（>62,000）导致在高纳摩尔浓度下有效抑制对NNRTI耐药的病毒分离株。此外，UC781与NNRTI考斯塔托利德联合使用时能够协同抑制HIV - 1复制，这表明UC781与RT的相互作用方式可能与其他UC类似物不同。UC化合物良好的抗HIV特性表明它们应被考虑用于进一步的临床开发。
