Synthesis and Biotransformation of Anti-HIV Prodrugs

尽管为艾滋病患者引入的抗艾滋病毒化疗的多种组合有效， 尽管艾滋病病毒感染的管理，但在艾滋病病毒化疗中仍然存在许多关键的未解决问题。显然 现有的药物并不总是有效的，主要是由于缺乏效力，耐药病毒的发展， 药代动力学，缺乏对病毒储库的渗透，影响药物安全性的药物相互作用，口服 生物利用度和HIV感染患者的依从性差。根据我们对人类的分子生物学知识， 艾滋病毒，药物化学知识，以及药理学方法，我们的团队是唯一有资格解决 这些挑战。该提案中涉及的一些问题是淋巴系统中的病毒复制， 有针对性的药物输送，痴呆症和大脑作为病毒库，病毒抗性和药物组合， 交互.我们在设计和合成更具选择性和有效的抗病毒药物方面的良好记录， 实现这些目标是既定的。在上一个资助期间，我们开发了一种有前途的前药，（-）- b-D-2，6-二氨基嘌呤二氧戊环（DAPD），目前正在进行Triangle的II期临床试验 大药厂DAPD不仅是一种有效的抗HIV药物，而且它已被证明具有良好的病毒抵抗性， 这是艾滋病患者挽救治疗所必需的。因此，DAPD 被FDA指定为“快速通道”化合物。为了进一步提高其效价、生物利用度， 和选择性靶向递送至淋巴系统和脑，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-D4 A、2 ′-F-D4 I 和2 ′ F-D4 G，其对突变病毒具有有效的抗病毒活性。然而，这些嘌呤核苷可能是有限的， 由于它们差的细胞转运，在本申请中，我们提出了合成各种前药 以改善效力以及药代动力学/药效学特征。最近，我们还发现了 D4 G前药（6-环丙基氨基-D4 G）的有效抗HIV活性，而D4 G本身对HIV几乎无活性。 HIV-1我们计划进行各种生物学评价，以确定这种前药作为临床药物的全部潜力。 候选人这种方法可以扩展到其他类别的抗病毒剂。总之，我们将继续 研究三类拟议的前药，以改善其在小鼠、大鼠和恒河猴中的药代动力学特征 猴子，以增强母体抗HIV药物的功效。如果在这些过程中发现任何有希望的前药， 研究，我们计划将其作为临床候选人。

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.