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: 8001786
• 负责人: John M Hilfinger
• 金额: $ 29.68万
• 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 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8001786
• 关键词: 9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine; 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）：由于抗病毒预防和先发制人治疗的广泛使用，人类巨细胞病毒（HCMV）疾病的发病率和严重程度及其间接影响已显着降低。然而，人们越来越认识到抗病毒药物耐药性。特别是，随着口服更昔洛韦 (GCV) 预防 HCMV 的出现，人们开始担心出现 GCV 耐药性 (GCV-R)。 GCV-R 可以用核苷酸磷酸盐药物成功治疗，例如西多福韦 (CDV) 和 9-(S)-(3-羟基-2-膦酰甲氧基-丙基)腺嘌呤 (HPMPA)。然而，这些药物作为口服治疗药物受到很大限制，因为作为一个整体，它们在口服给药时吸收很差。我们开发了一种前药策略，旨在改善核苷酸膦酸酯药物 CDV 和 HPMPA 的口服吸收，使它们成为有效的抗 HCMV 口服治疗剂。在该项目的第一阶段部分，我们建议合成一系列新型 CDV 和 HPMPA 前药，并评估它们对敏感和 GCV-R 耐药 CMV 菌株的稳定性、代谢和抗病毒活性。将测试那些表现出良好稳定性和简化代谢的前药的口服生物利用度。这项工作将为开发有效的口服抗更昔洛韦耐药 HCMV 药物奠定科学基础。对于这个项目，我们与南加州大学的 Charles McKenna 教授（前药设计和合成）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：对有效对抗人类巨细胞病毒耐药株的新药的需求日益增加，随着针对该病毒的长期治疗方法的开发，这种病毒株的数量也越来越多。已有一系列新药上市，但由于口服吸收不好，不适合商业化。因此，这项工作的目标是修改这些新药，使其口服时吸收良好，并且能有效对抗人类巨细胞病毒。