NOVEL CONTRACEPTIVES WITH ANTI-HIV ACTIVITY

描述：（改编自申请人摘要） 人类免疫缺陷病毒（HIV）是艾滋病的病原体， 这是育龄妇女死亡率增长最快的原因。 异性性传播占全世界所有艾滋病毒感染的80%以上- 艾滋病毒/艾滋病感染者的比例越来越高， 美国的目前使用的局部阴道杀菌剂， 壬苯醇醚-9（N-9）-一种基于去污剂的杀精子病毒剂， 它的高避孕失败率也会导致粘膜糜烂， 局部炎症，可能会增加艾滋病毒传播的风险。 因此，新的，有效的，安全的，女性控制的阴道 迫切需要杀微生物剂来遏制艾滋病毒的阴道传播 感染试图找出一种杀微生物剂避孕药 有可能预防艾滋病毒的性传播， 提供生育控制，一系列溴-甲氧基取代的新的 抗HIV药物叠氮胸苷（AZT;齐多夫定）的衍生物， 合成并检测了双重抗HIV活性和杀精活性 活动两个先导化合物，WHI-05和WHI-07，表现出有效的抗- 以及杀精子活性。体内杀精结果 在小鼠模型中的有效性和缺乏局部毒性表明， SHI-05和WHI-07作为双重功能，将是有吸引力的候选物 阴道杀菌剂申请人现在提出临床前 研究进一步评估这些双重的临床潜力， 功能AZT衍生物。具体目标是：（一）评估 WHI-05和WHI-07在兔中的体内避孕活性;（ii） 评价WHI-05和WHI-07预防经粘膜和 猫免疫缺陷病毒的围产期传播 自然宿主模型;（iii）评估WHI-05和WHI-07的能力 防止HIV-1在黑猩猩中的经粘膜传播， 替代宿主模型;和（iv）进行体内发育， WHI-05和WHI-07的生殖毒理学和致癌性研究 在啮齿动物模型中。双功能阴道杀菌剂的研制 遏制艾滋病毒传播和预防生育将是一个重大的 采取措施保护性活跃妇女免受阴道艾滋病毒感染 传输关于WHI-05的体内功效的临床前数据和 WHI-07将是必要的，以进一步探索这些小说的效用 用于人类患者临床研究的药物。

DESCRIPTION: (Adapted from Applicant's Abstract) Human immunodeficiency virus (HIV), the causative agent of AIDS is the fastest growing cause of death in women of reproductive age. Heterosexual transmission accounts for >80% of all HIV infections world- wide, and constitutes a growing proportion of new HIV infections in the United States. The currently used topical vaginal microbicide, nonoxynol-9 (N-9)-a detergent-based virucidal spermicide in addition to its high contraceptive failure rates also causes mucosal erosion and local inflammation which might increase the risk of HIV transmission. Therefore, new, effective, safe, and female-controlled vaginal microbicides are urgently needed to curb vaginal transmission of HIV infection. With an attempt to identify a microbicide contraceptive potentially capable of preventing sexual transmission of HIV as well as providing fertility control, a series of bromo-methoxy substituted novel derivatives of the anti-HIV drug, azidothymidine (AZT; zidovudine), were synthesized and examined for dual anti-HIV activity and spermicidal activity. Two lead compounds, WHI-05 and WHI-07, exhibited potent anti- HIV as well as spermicidal activity. Results of in vivo spermicidal efficacy and lack of local toxicity in the mouse model indicated that SHI-05 and WHI-07 would be attractive candidates as dual function vaginal microbicides. The applicants are now proposing preclinical studies to further evaluate the clinical potential of these dual- function AZT derivatives. The specific aims are: (i) to evaluate the in vivo contraceptive activity of WHI-05 and WHI-07 in rabbits; (ii) to evaluate the ability of WHI-05 and WHI-07 to prevent transmucosal and perinatal transmission of feline immunodeficiency virus in cats as the natural host model; (iii) to evaluate the ability of WHI-05 and WHI-07 to prevent transmucosal transmission of HIV-1 in chimpanzees as a surrogate host model; and (iv) to perform in vivo developmental, reproductive toxicology, and carcinogenesis studies of WHI-05 and WHI-07 in rodent models. The development of dual function vaginal microbicides to curb HIV transmission and prevent fertility will be a significant step forward to protect sexually active women from vaginal HIV transmission. The preclinical data on in vivo efficacies of WHI-05 and WHI-07 will be essential to further explore the utility of these novel drugs for clinical studies in human patients.