New Prodrug Strategies for Cidofovir Designed for Mitigating First-Pass Metabolism

摘要 双链DNA病毒是导致人类许多疾病的原因。虽然许多人 这些感染表现出长期的持续性或潜伏性感染，其中一些感染可以成为 免疫功能低下的患者病情严重，危及生命。目前的治疗方法是有效的 (如西多福韦、更昔洛韦和磷甲酸钠)抗DNA病毒，但受到一些 不良副作用。例如，西多福韦(CDV，Vistie®)是一种核苷膦酸类药物 对DNA病毒具有广谱的抗病毒活性。一种有效的病毒DNA抑制剂 聚合酶，CDV对疱疹病毒特别有效，并被用于治疗 艾滋病相关巨细胞病毒(CMV)视网膜炎。然而，与更昔洛韦和磷甲环胺一样，CDV也是一种 口服生物利用度差的极性分子，因此必须静脉给药。 此外，由于急性肾毒性发生率较高，其剂量和临床应用受到限制。 因此，需要改进的治疗方法来治疗免疫功能低下的患者和其他高 风险人群。前药，如布林多福韦和CDV-酪氨酸连接的烷基酰胺 由我们团队开发的，已经开发出将CDV结合成可代谢切割的， 专为增加细胞摄取而设计的亲脂载体。在细胞内，CDV然后被酶解 从前药中释放出来，然后代谢成活性的病毒DNA聚合酶抑制剂 西多福韦二磷酸(CDV-PP)。虽然这些类比在以下方面显示出显著的改进 对多种DNA病毒的抗病毒效力，不幸的是，它们在体内肝脏中表现出很高的活性 通行证。难以解释这些肝脏形成的几种代谢物 通路构成了一个重大的发展挑战，并限制了活性代谢物的数量 到达被病毒感染的细胞。为了解决这一限制，我们建议综合和 评估针对DNA病毒的新的前药。这些新的类比将被设计成保持 高抗病毒活性，同时减轻肝脏清除。为了实现这一目标，我们在本报告中概述了 建议，将评估插入在末端的新陈代谢抗性化学取代基 具有亲脂性的烷基链。在此过程中，我们将把新的衍生品与cmx-001进行比较。 用于细胞通透性和肝微粒体的代谢稳定性。

Abstract Double-stranded DNA viruses are responsible for many diseases in humans. While many of these exhibit long-term persistent or latent infections, some of these infections can become severe and life-threatening in immunocompromised patients. Current treatments are effective (e.g. Cidofovir, ganciclovir and foscarnet) against DNA viruses, but are limited by a number of undesired side effects. For example, Cidofovir (CDV, Vistide®) is a nucleoside phosphonate that has broad spectrum antiviral activity against DNA viruses. A potent inhibitor of viral DNA polymerase, CDV is particularly active against herpesviruses and is indicated for treatment of AIDS-related cytomegalovirus (CMV) retinitis. However, like ganciclovir and foscarnet, CDV is a polar molecule with poor oral bioavailability and therefore must be administered intravenously. Moreover, its dose and overall clinical utility is limited by high occurrence of acute nephrotoxicity. As such, improved therapies are needed to treat immunocompromised patients and other high risk populations. Prodrugs, such as Brincidofovir and CDV-tyrosine-linked alkyl amides developed by our group, have been developed that conjugate CDV to a metabolically-cleavable, lipophilic carrier designed to increase cellular uptake. Intracellularly, CDV is then enzymatically released from the prodrug and then metabolized to the active viral-DNA polymerase inhibitor Cidofovir diphosphate (CDV-PP). While these analogs exhibited significant improvements in antiviral potency against numerous DNA viruses, they unfortunately exhibited high in vivo hepatic clearance. The difficulty in accounting for the several metabolites formed from these hepatic pathways poses a major development challenge and limits the amount of active metabolite reaching the virus-infected cells. To address this limitation, we propose to synthesize and evaluate new prodrugs against DNA viruses. These new analogs will be designed to maintain high antiviral activity while mitigating hepatic clearance. To achieve this, our goal outlined in this proposal, will be to evaluate metabolically-resistant chemical substituents inserted at the terminus of the lipophilic alkyl chain. In doing so, we will compare the new derivatives against CMX-001 for cell permeability and for metabolic stability in liver microsomes.