SYNTHESIS OF NEW NNRTIS FOR THE TREATMENT OF AIDS

描述：（改编自申请人的摘要） 逆转录酶抑制剂（NNRTI）代表了一组不同的 在治疗艾滋病方面具有潜在价值的化合物。新的兴趣 在这些化合物中， 存在克服抗性病毒株出现的策略 这通常是由其使用引起的。其中包括切换到另一个 病毒对NNRTI保持敏感，使用更高剂量的 针对抗性菌株的NNRTI，以及组合的使用 引发突变的药剂相互抵消。然而，在这方面， 为了全面实施这些战略，需要建立新的非核技术研究机构 它会有独特的耐药突变模式， 降低诱发病毒耐药性的可能性。申请人的 一个研究小组最近发现了一类新的NNRTI， 烯基二芳基甲烷（亚当斯）。迄今为止，已对一名ADAM进行了调查， 详细它显示出与AZT的协同活性， 更有效地对抗抗AZT病毒。进一步努力 增加原始先导化合物的效力导致了 第二种ADAM抑制HIV-1的细胞病变效应，EC 50 值为13 nM。对这些问题进行更有针对性的调查 为了获得额外亚当斯 具有增强的效力和治疗指数，以及独特的 耐药突变模式和抗病毒株的活性 对其他非核苷类逆转录酶抑制剂有抵抗力的病毒。一个工作假设的 申请人的观点是，增加的构象自由度将与 抵抗力下降。新的亚当斯被设计成 借助计算机图形学分子建模， HIV-1逆转录病毒NNRTI结合位点的特定氨基酸残基 录酶分析这些假设的结构模型 转化为酶抑制和抗病毒活性， 结构-活性关系的构建， 在设计进一步的潜在价值的非放射性治疗， 艾滋病此外，这里提出的研究应导致 合成化合物的价值，以获得有关 结合复合物的结构。新的亚当斯可以很容易地制备 通过使用醛和适当的醛之间的Wittig反应， 取代的二苯甲酮，他们将在各种测试， 代表复制周期中关键事件的机制测定 病毒，以便精确地定义它们的作用机制。

DESCRIPTION: (Adapted from Applicant's abstract) The non-nucleoside reverse transcriptase inhibitors (NNRTIs) represent a diverse set of compounds of potential value in the treatment of AIDS. Renewed interest in these compounds has resulted from the realization that several viable strategies exist for overcoming the emergence of resistant viral strains that usually result from their use. These include switching to another NNRTI to which the virus has remained sensitive, using higher doses of the NNRTI against the resistant strain, and employment of combinations of agents which elicit mutations that counteract one another. However, in order to fully implement these strategies, new NNRTIs are required which will have unique patterns of resistance mutations, as well as a diminished liability for eliciting viral resistance. The applicant's research group recently discovered a novel class of NNRTIs, the alkenyldiarylmethanes (ADAMs). To date, one ADAM has been investigated in detail. It displayed synergistic activity with AZT and was found to be more effective against an AZT-resistant virus. Further work to increase the potency of the original lead compound has resulted in a second ADAM with inhibits the cytopathic effect of HIV-1 with an EC50 value of 13 nM. A more focused and concentrated investigation of these compounds is presently indicated in order to obtain additional ADAMs with enhanced potencies and therapeutic indices, as well as unique patterns of resistance mutations and activities against viral strains that are resistant to other NNRTIs. A working hypothesis of the applicant is that increased conformational freedom will be associated with decreased resistance liability. The new ADAMs have been designed with the aid of computer graphics molecular modeling in order to target specific amino acid residues in the NNRTI binding site of HIV-1 reverse transcriptase. An analysis of how these hypothetical structural models translate into enzyme inhibition and antiviral activities will allow the construction of structure-activity relationships that will be of value in the design of further NNRTIs of potential value in the treatment of AIDS. In addition, the studies proposed here should result in the synthesis of compounds of value in gaining information about the structures of the bound complexes. The new ADAMs can be prepared readily by employing Wittig reactions between aldehydes and appropriately substituted benzophenones, and they will be tested in a variety of mechanistic assays representing key events in the replication cycle of the virus in order to define precisely their mechanism of action.