Synthesis and Biotransformation of Anti-HIV Prodrugs

尽管针对艾滋病引入的多种抗艾滋病毒化疗组合有效 在艾滋病毒感染的管理方面，艾滋病毒化学治疗方面仍有一些关键问题悬而未决。很明显 现有药物并不总是有效的，主要是由于缺乏效力，产生抗药性病毒，质量不佳 药物动力学，缺乏对病毒库的渗透，药物相互作用影响药物的安全性，口服 艾滋病毒感染者的生物利用度和依从性差。基于我们对分子生物学的了解 艾滋病毒，药物化学知识，以及药理学方法，我们的小组是唯一有资格解决的问题 这些挑战。这项提案中涉及的一些问题是淋巴系统中的病毒复制， 靶向药物传递、痴呆症和作为病毒储存库的大脑、病毒耐药性和药物组合 互动。我们在设计和合成更具选择性和效力的抗病毒药物方面取得了良好的业绩记录 实现这些目标是既定的。在之前的资助期间，我们开发了一种很有前途的前药，(-)- B-D-2，6-二氨基-2，6-二氨基二氧戊烷(DAPD)，目前正在进行TriangleII期临床试验 制药公司。DAPD不仅是一种有效的抗艾滋病毒药物，而且它还表现出良好的病毒抗药性。 体外和体内的概况，这是抢救艾滋病患者所必需的。因此，洛杉矶警察局已经 被美国食品和药物管理局指定为“快速通道”化合物。为了进一步提高药效，生物利用度， 以及选择性靶向淋巴系统和大脑的给药，我们提出了几种Dapd的前药。最近， 我们还发现了一类新的2‘-氟不饱和核苷的D-对映体，包括2’-F-D4A，2‘-F-D4L 和2‘F-D4G，对突变病毒有很强的抗病毒活性。然而，这些嘌呤核苷可能是有限的。 作为有用的试剂，因为它们的细胞传输能力很差。在这一应用中，我们提出了合成各种前药 以改善药效以及药代动力学/药效学特征。最近，我们还发现了一种 D4G前药(6-环丙氨基-D4G)具有很强的抗HIV活性，而D4G本身对HIV几乎没有活性 HIV-1。我们计划进行各种生物学评价，以确定该前药作为临床应用的全部潜力。 候选人。这种方法可以推广到其他类别的抗病毒药物。总而言之，我们将继续 研究三类前药改善其在小鼠、大鼠和恒河猴体内的药代动力学 猴子能增强家长抗HIV药物的功效。如果在这些过程中发现任何前药有希望 随着研究的深入，我们计划将他们提升为临床候选患者。

Despite the effectiveness of multiple combinations of anti-HIV chemotherapy that was introduced for the management of HIV infection, there are still a number of critical unresolved issues in HIV chemotherapy. It is clear that existing drugs are not always effective primarily due to lack of potency, development of resistant virus, poor pharmacokinetics, lack of penetration into virus reservoirs, drug interactions affecting safety of the drug, oral bioavailability, and poor compliance by HIV infected patients. Based on our knowledge of the molecular biology of HIV, medicinal chemistry know-how, as well as pharmacological approach, our group is uniquely qualified to tackle these challenges. Some of the issues addressed in this proposal are the viral replication in lymphatic systems, targeted drug delivery, dementia and the brain as a viral reservoir, viral resistance and drug combination and interactions. Our proven track record in designing and synthesizing more selective and potent antiviral agents to achieve these goals is well established. During the previous funding period, we developed a promising prodrug, (-)- b-D-2,6-diaminopurine dioxolane (DAPD), which is currently undergoing Phase II clinical trials by Triangle Pharmaceuticals. DAPD is not only a potent anti-HIV agent, but also it has demonstrated a favorable viral resistant profile in vitro as well as in vivo, which is necessary for salvage therapy for AIDS patients. Therefore, DAPD has been designated as a "fast-track" compound by the FDA. In order to further improve the potency, bioavailability, and selective targeted delivery to the lymphatic system and brain, we propose several prodrugs of DAPD. Recently, we also discovered a new class of D-enantiomers of 2'-fluoro-unsaturated nucleosides, including 2'-F-D4A, 2'-F-D4l and 2'F-D4G with potent antiviral activity against mutant viruses. However, these purine nucleosides may be limited as useful agents due to their poor cellular transport. In this application, we proposed to synthesize various prodrugs to improve the potency as well as pharmacokinetic/pharmacodynamic profiles. Very recentiy, we also discovereda potent anti-HIV activity of D4G prodrug (6-cyclopropylamino-D4G), while D4G itself is practically inactive against HIV-1. We plan to conduct various biological evaluation to determine the full potential of this prodrug as a clinical candidate. This approach may be extended to other classes of antiviral agents. In summary, we will continue to study three classes of proposed prodrugs to improve their pharmacokinetics profiles in mice, rats and rhesus monkeys to enhance the efficacy of parent anti-HIV agents. If any prodrugs are found to be promising during these studies, we plan to advance them as clinical candidates.