METHYLENECYCLOPROPANE ANALOGS AND PRODRUGS FOR HCMV

HCMV 的亚甲基环丙烷类似物和前药

• 批准号: 6254607
• 负责人: JIRI ZEMLICKA
• 金额: $ 18.73万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2003-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6254607
• 关键词: antiviral agents; chemical registry /resource; cyclopropanes; cytomegalovirus; drug design /synthesis /production; nucleoside analog; prodrugs

Selected 6-amino- and 2-amino-6-substituted purine Z- methylenecyclopropane nucleoside analogues (mostly S-enantiomers) will be prepared for biological evaluation as potential drugs against human cytomegalovirus (HCMV). New 2,6-disubstituted purine methylenecyclopropanes will be synthesized for studies of structure- activity relationships. Several types of prodrugs of enantiomeric Z- methylenecyclopropane analogues will also be prepared for a detailed in vitro and in vivo evaluation. The major aim of the project is to provide multigram quantities of analogues in enantiopure form (lipophilic phosphate prodrugs as two diastereoisomers each) to permit (i) their evaluation in vitro against wild type and mutated forms of cytomegalovirus (CMV), (ii) in vivo studies in animals infected with CMV, (iii) investigation of cross-resistance with current drugs and (iv) studies of mechanism of action of these analogues. These studies are relevant for preclinical development of methylenecyclopropane analogues of nucleosides as anti-HCMV drugs.

选定的6-氨基和2-氨基-6二取代的嘌呤Z-甲基丙烷丙烷核苷类似物（主要是S-替象体）将准备用于生物学评估，以作为对人巨细胞病毒（HCMV）的潜在药物。 将合成新的2,6二取代的嘌呤甲基苯甲丙烷丙烷，以研究结构活性关系。还将为详细的体外和体内评估准备几种类型的对映体Z-甲基丙烷类似物的前药。 The major aim of the project is to provide multigram quantities of analogues in enantiopure form (lipophilic phosphate prodrugs as two diastereoisomers each) to permit (i) their evaluation in vitro against wild type and mutated forms of cytomegalovirus (CMV), (ii) in vivo studies in animals infected with CMV, (iii) investigation of cross-resistance with current drugs and （iv）研究这些类似物的作用机理。 这些研究与核苷作为抗HCMV药物的甲基苯丙烷类似物的临床前发展有关。