Synthesis of New NNRTLs for the Treatment of AIDS

描述(由申请人提供)： 目前需要一种新型的非核苷类HIV-1逆转录酶抑制剂(NNRTI)，其具有比现有NNRTI更低的毒性，2)具有独特的抗药性突变特征并且对对现有NNRTI具有抗药性的突变逆转录酶保持活性，3)当与其他抗HIV药剂结合使用时具有抑制耐药病毒株的能力，4)与其他抗HIV药剂结合具有协同抗HIV活性，5)代谢比现有ADAM更稳定并因此具有增强的生物利用度，6)具有与各种HIV-1毒株相比的广泛活性，和7)对RT具有高亲和力，因此具有高抗HIV效力的潜力。我们的研究小组最近报道了一系列新型的烯基二芳甲烷(ADAM)NNRTIs的设计和合成，这些NNRTIs是HIV-1细胞病变效应的有效抑制剂。虽然一些ADAMS在低纳摩尔浓度下抑制了CEM-SS细胞培养中HIV-1RF的细胞病变效应，但ADAMS的潜在治疗作用因三个甲酯部分的存在而受到影响，这些甲酯部分很容易被血浆酯酶水解。因此，本项目的主要目标是为这三种不稳定的酯找到合适的替代品，这些酯在代谢上将是稳定的，并将保留母体化合物的强大抗艾滋病毒活性。初步研究表明，恶唑烷酮和甲醚取代甲酯具有良好的活性，并提出了多种新的代谢稳定基团。这些取代物包括乙基酮、异丁烯、烯醇醚、醚、乙烯基酮、正丙基、α、α-二氟酮、二氟烯醚、四氟异丁烯、二氟异丁烯、亚胺基氟化物、酰胺、硫酯、硫代酯和二硫酯取代物。提出了含有这些结构简单的甲酯取代物的亚当斯的合成方法。新的ADAMS的水解稳定性将在人体血浆中进行研究。此外，新的ADAMS的抗艾滋病毒活性将在多种生物系统中进行测定。这些化合物作为多种HIV-1毒株的细胞病变效应的抑制剂的效力将在细胞培养中确定。这些化合物在未感染的淋巴细胞中的细胞毒性也将被调查。ADAMS的酶抑制活性将在使用野生型和突变蛋白的无细胞系统中建立。作用机制研究将包括添加时间(时间进程)研究以及使用代表病毒复制周期不同阶段的目标的若干检测中对化合物的检查。将确定这些化合物与现有抗艾滋病毒药物的协同活性。将研究ADAMS与NNRTI耐药病毒的活性。新亚当斯的水溶解度将被准确测量。

DESCRIPTION (provided by applicant): A current need exists for novel non-nucleoside HIV-1 reverse transcriptase inhibitors (NNRTIs) that: 1) have lower toxicities than the existing NNRTIs, 2) have unique resistance mutation profiles and remain active against mutant reverse transcriptases that are resistant to the existing NNRTIs, 3) have the ability to suppress the emergence of resistant viral strains when used in combination with other anti-HIV agents, 4) have synergistic anti-HIV activity in combination with other anti-HIV agents, 5) are metabolically more stable than the existing ADAMs and therefore have enhanced bioavailabilities, 6) have a wide range of activity vs. various HIV-1 strains, and 7) have high affinities for RT, and therefore have the potential for high anti-HIV potency. Our research group has recently reported the design and synthesis of a novel series of alkenyldiarylmethane (ADAM) NNRTIs that are potent inhibitors of the cytopathic effect of HIV-1. Although some of the ADAMs inhibit the cytopathic effect of HIV-1RF in CEM-SS cell culture at low nanomolar concentrations, the potential therapeutic utility of the ADAMs is compromised by the presence of three methyl ester moieties that are readily hydrolyzed by plasma esterases. Consequently, the main goal of the present project is to find suitable replacements for these three labile esters that will be metabolically stable and will also retain the potent anti-HIV activity of the parent compound. Preliminary studies have shown promising activity resulting from oxazolidinone and methyl ether replacements of the methyl esters, and a variety of additional metabolically stable moieties are proposed. These include ethyl ketone, isobutylene, enol ether, ether, vinyl ketone, n-propyl, alpha, alpha -difluoroketone, difluoroenol ether, tetrafluoroisobutylene, difluoroisobutylene, imidoyl fluoride, amide, thioester, thionoester, and dithioester replacements. Syntheses are proposed for ADAMs containing each of these structurally simple methyl ester replacements. The hydrolytic stabilities of the new ADAMs will be investigated in human plasma. In addition, the anti-HIV activities of the new ADAMs will be determined in a variety of biological systems. The potencies of the compounds as inhibitors of the cytopathic effect of a variety of HIV-1 strains will be determined in cell culture. The cytotoxicities of the compounds in uninfected lymphocytes will also be investigated. The enzyme inhibitory activities of the ADAMs will be established in cell-free systems using both wild type and mutant proteins. Mechanism of action studies will include both time-of-addition (time course) studies as well as the examination of the compounds in a number of assays employing targets that represent various stages in the replication cycle of the virus. The synergistic activities of the compounds with existing anti-HIV agents will be established. The activities of the ADAMs vs. NNRTI resistant viruses will be investigated. The aqueous solubilities of the new ADAMs will be measured accurately.