SYNTHESIS OF NEW NNRTIS FOR THE TREATMENT OF AIDS

描述：(改编自申请人的摘要)非核苷 逆转录酶抑制物(NNRTI)代表一组不同的 在治疗艾滋病方面有潜在价值的化合物。重新燃起的兴趣 在这些化合物中产生了几种可行的 有克服耐药病毒株出现的策略 这通常是由于它们的使用造成的。这些措施包括切换到另一个 病毒仍然敏感的NNRTI，使用更高剂量的 抗性品系的NNRTI及其组合的利用 引发突变并相互抵消的药剂。然而， 为了充分实施这些战略，需要新的NNRTI 它将具有独特的抗药性突变模式，以及 减少了引发病毒抗药性的风险。申请人的 研究小组最近发现了一类新的NNRTI，即 烯基二芳基甲烷(亚当斯)到目前为止，一名亚当已经被调查 详细地说。它与AZT显示出协同活性，并被发现 更有效地对抗抗AZT病毒。进一步的工作是 增加了原铅化合物的效力，导致 第二，ADAM用EC50抑制HIV-1的细胞病变效应 价值13海里。对这些问题进行更有重点和更集中的调查 化合物目前表明是为了获得更多的亚当斯 具有增强的效力和治疗指数，以及独特的 病毒株的耐药突变模式及其活性 对其他NNRTI具有抵抗力。一种有效的假说 申请者是增加的构象自由将与 减少了抵抗力。新的亚当斯已经设计好了 借助计算机图形学分子建模，以达到靶向 HIV-1逆转录病毒NNRTI结合部位的特异性氨基酸残基 转录酶。分析这些假设的结构模型是如何 转化为酶抑制和抗病毒活性将使 构建有价值的结构-活动关系 在进一步的NNRTI的设计中具有潜在的治疗价值 艾滋病。此外，这里提出的研究应该会导致 化合物的合成对获取有关化合物的信息有价值 结合络合物的结构。新的亚当斯很容易制备。 通过利用醛和适当的Wittig反应 取代的二苯甲酮，它们将在各种 代表复制周期中的关键事件的机械性分析 为了准确地定义它们的作用机制，我们需要对病毒进行研究。

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.