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

旨在减轻首过代谢的西多福韦新前药策略

• 批准号: 9436472
• 负责人: Elke Lipka
• 金额: $ 10.12万
• 依托单位: TSRL, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9436472
• 关键词: Accounting; Acquired Immunodeficiency Syndrome; Acute; Address; Adverse effects; Alabama; Amides; Analytical Chemistry; Antiviral Agents; Back; Biological Availability; Budgets; Cells; Chemicals; Cidofovir; Clinical; Complex; Computer Simulation; Contracts; Cytomegalovirus; Cytomegalovirus Infections; Cytomegalovirus Retinitis; DNA Polymerase Inhibitor; DNA Viruses; DNA-Directed DNA Polymerase; Development; Diphosphates; Disease; Dose; Double Stranded DNA Virus; Drug Kinetics; Ensure; Evaluation; Exhibits; Foscarnet; Foundations; Funding; Ganciclovir; Generations; Glucuronides; Goals; Grant; Health Services; Hepatic; Herpesviridae; Human; Immune system; Immunocompromised Host; In Vitro; Infection; Intracellular Transport; Intravenous; Laboratories; Life; Link; Liver; Liver Microsomes; Measures; Medical; Metabolic; Metabolism; Michigan; National Institute of Allergy and Infectious Disease; Nucleosides; Oral; Oxides; Pathway interactions; Permeability; Pharmaceutical Chemistry; Prodrugs; Property; Pulmonary Inflammation; Rattus; Research Contracts; Research Proposals; Resistance; Retinitis; Services; Synthesis Chemistry; Techniques; Therapeutic; Transplant Recipients; Tyrosine; Universities; Virus; Virus Diseases; Virus Inhibitors; alkyl group; analog; base; chronic infection; clinical development; conventional therapy; cytotoxic; design; high risk population; improved; in vivo; indexing; latent infection; lead candidate; lipophilicity; liquid chromatography mass spectrometry; liver metabolism; nephrotoxicity; phosphonate; preclinical toxicity; prospective; screening; uptake; viral DNA; virology

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.

抽象的 双链DNA病毒是导致人类许多疾病的原因。虽然许多 这些表现出长期持续性或潜伏性感染，其中一些感染可能会成为 免疫功能低下的患者病情严重并危及生命。目前治疗有效 （例如西多福韦、更昔洛韦和膦甲酸）对抗 DNA 病毒，但受到一些限制 不良的副作用。例如，西多福韦（CDV，Vistide®）是一种核苷膦酸酯， 对 DNA 病毒具有广谱抗病毒活性。病毒 DNA 的有效抑制剂 CDV 聚合酶对疱疹病毒特别有效，可用于治疗 艾滋病相关巨细胞病毒（CMV）视网膜炎。然而，与更昔洛韦和膦甲酸一样，CDV 是一种 极性分子口服生物利用度差，因此必须静脉注射。 此外，其剂量和总体临床效用因急性肾毒性的高发生率而受到限制。 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危人群 危险人群。前药，例如布西多福韦和 CDV-酪氨酸连接的烷基酰胺 由我们小组开发的，已开发出将 CDV 与代谢可裂解的、 旨在增加细胞摄取的亲脂性载体。 CDV 在细胞内被酶促 从前药中释放出来，然后代谢为活性病毒 DNA 聚合酶抑制剂 西多福韦二磷酸（CDV-PP）。虽然这些类似物在以下方面表现出显着的改进 对多种 DNA 病毒具有抗病毒效力，不幸的是它们在体内表现出高肝 清除。难以解释这些肝脏形成的几种代谢物 途径构成了重大的开发挑战并限制了活性代谢物的数量 到达被病毒感染的细胞。为了解决这个限制，我们建议综合和 评估针对 DNA 病毒的新前药。这些新的类似物将被设计为维持 高抗病毒活性，同时减轻肝脏清除率。为了实现这一目标，我们在此概述了目标 建议，将评估插入末端的耐代谢化学取代基 亲脂性烷基链。在此过程中，我们将新的衍生物与 CMX-001 进行比较 用于细胞通透性和肝微粒体的代谢稳定性。