Novel prodrugs for treatment of human CMV infection

用于治疗人类巨细胞病毒感染的新型前药

• 批准号: 8078923
• 负责人: John M Hilfinger
• 金额: $ 29.47万
• 依托单位: TSRL, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8078923
• 关键词: Adenine; Antiviral Agents; Biological; Biological Availability; California; Cell Membrane Permeability; Cells; Charge; Cidofovir; Collaborations; Cytomegalovirus; Cytosine; Development; Disease; Drug Kinetics; Drug resistance; Evaluation; Foundations; Ganciclovir; Goals; Human; Human Cell Line; Incidence; Infection; Intestines; Membrane; Metabolism; Michigan; Modification; Nucleosides; Nucleotides; Oral; Parents; Pharmaceutical Preparations; Phase; Phosphorylation; Phosphotransferases; Prodrugs; Prophylactic treatment; Research; Resistance; Series; Severities; Site; Testing; Therapeutic; Therapeutic Agents; Universities; Viral Drug Resistance; Virus; Work; absorption; adenine analog; analog; commercialization; cytotoxicity; design; improved; innovation; novel; phosphonate; public health relevance; resistant strain; treatment strategy

DESCRIPTION (provided by applicant): As a result of the widespread use of antiviral prophylaxis and pre-emptive therapy, the incidence and severity of human cytomegalovirus (HCMV) disease and its indirect effects have been significantly reduced. However, there is an increasing recognition of antiviral drug resistance. In particular, with the advent of oral ganciclovir (GCV) prophylaxis against HCMV, concerns about emergence of GCV resistance (GCV-R) have been raised. GCV-R can be successfully treated with nucleotide phosphonate drugs such as Cidofovir (CDV) and 9-(S)-(3- hydroxy-2-phosphonomethoxy-propyl)adenine (HPMPA). However, these drugs are significantly limited as oral therapeutics because, as a group, they are poorly absorbed when administered orally. We have developed a prodrug strategy designed to improve the oral absorption of the nucleotide phosphonate drugs, CDV and HPMPA, such that they will be effective anti-HCMV oral therapeutic agents. In the phase 1 portion of the project, we propose to synthesize a novel series of CDV and HPMPA prodrugs and evaluate their stability, metabolism and antiviral activity against sensitive and GCV-R resistant strains of CMV. Those prodrugs showing good stability and simplified metabolism will be tested for oral bioavailability. This work will lay the scientific foundation for development of an effective, oral agent against ganciclovir resistant HCMV. For this project, we have established collaborations with Prof. Charles McKenna (prodrug design and synthesis) at the University of Southern California and Prof. John Drach (virological studies) at the University of Michigan. PUBLIC HEALTH RELEVANCE: There is an increasing need for new drugs that are effective against drug-resistant strains of the human cytomegalovirus that are becoming more numerous as long term treatments against the virus are developed. A series of new drugs is available but they are not suitable for commercialization because they are not well absorbed when given orally. Thus, the goal of this work is to modify these new drugs such that they are well absorbed when taken orally and will be effective against the human cytomegalovirus.

描述（由申请人提供）：由于广泛使用抗病毒预防和先发制人治疗，人类巨细胞病毒（HCMV）疾病的发生率和严重程度及其间接作用已大大降低。但是，人们对抗病毒抗药性的认识越来越多。特别是，随着口服Ganciclovir（GCV）预防HCMV的出现，已经提出了对GCV抗性（GCV-R）出现的担忧。 GCV-R可以用核苷酸磷酸药物（例如Cidofovir（CDV）和9-（S） - （3-羟基-2-磷酸磷酸磷灰素）腺嘌呤（HPMPA）成功治疗。但是，这些药物被显着限制为口服治疗剂，因为作为一个口服时，它们的吸收不佳。我们已经制定了一种前药策略，旨在改善核苷酸磷酸药物CDV和HPMPA的口服吸收，从而使它们具有有效的抗HCMV口服治疗剂。在项目的第1阶段部分中，我们建议合成一系列新型CDV和HPMPA前药，并评估其稳定性，代谢和抗病毒活性，以抗敏感和GCV-R耐药菌株CMV。那些表现出良好稳定性和简化代谢的前药将用于口服生物利用度。这项工作将奠定针对抗Ganciclovir耐药HCMV的有效口服剂的科学基础。对于这个项目，我们已经与南加州大学的Charles McKenna教授（Proprug Design and Synthesis）和密歇根大学的John Drach教授（病毒学研究）建立了合作。 公共卫生相关性：对新药的需求越来越有效，这些药物对人类巨细胞病毒的抗药性菌株有效，随着对病毒的长期治疗的发展，这些药物的需求越来越多。一系列新药可用，但不适合商业化，因为口服时它们没有很好地吸收。因此，这项工作的目的是修改这些新药，以使它们在口服时被良好吸收，并且对人类巨细胞病毒有效。