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

摘要 双链DNA病毒是人类许多疾病的罪魁祸首。虽然许多 这些表现出长期持续性或潜伏性感染，其中一些感染可以成为 严重的和危及生命的免疫功能低下的患者。目前的治疗方法是有效的 (e.g.西多福韦、更昔洛韦和膦甲酸）对抗DNA病毒，但受到许多 不良副作用。例如，西多福韦（CDV，Vistide®）是核苷膦酸酯， 具有广谱抗DNA病毒活性。一种有效的病毒DNA抑制剂 聚合酶，CDV对疱疹病毒特别有活性，并适用于治疗 艾滋病相关的巨细胞病毒（CMV）视网膜炎。然而，像更昔洛韦和膦甲酸一样，CDV是一种 口服生物利用度差的极性分子，因此必须静脉内给药。 此外，其剂量和总体临床效用受到急性肾毒性高发生率的限制。 因此，需要改进的疗法来治疗免疫功能低下的患者和其他高免疫缺陷的患者。 风险人群。前药，如布林西多福韦和CMV-酪氨酸连接的烷基酰胺 由我们的小组开发的，已经开发出将CDV缀合到可代谢裂解的， 亲脂性载体，旨在增加细胞吸收。在细胞内，CDV然后被酶促地 从前药中释放，然后代谢为活性病毒DNA聚合酶抑制剂 西多福韦二磷酸盐（CDV-PP）。虽然这些类似物在以下方面表现出显著的改善： 尽管它们对许多DNA病毒具有抗病毒效力，但不幸的是，它们在体内肝脏中表现出高的抗病毒效力。 间隙解释这些肝细胞形成的几种代谢物的困难在于， 途径构成了一个主要的开发挑战，并限制了活性代谢物的量 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 评估抗DNA病毒的新前药。这些新的类似物将被设计为保持 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 建议，将评估代谢抗性化学取代基插入在末端 亲脂性的烷基链。在此过程中，我们将比较新的衍生品与CMX-001 用于肝微粒体中的细胞渗透性和代谢稳定性。

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.