NOVEL CONTRACEPTIVES WITH ANTI-HIV ACTIVITY

描述：(改编自申请者摘要) 人类免疫缺陷病毒(HIV)，艾滋病的病原体是 育龄妇女死亡原因增长最快。 异性传播占全球艾滋病毒感染总数的80%- 广泛传播，在全球艾滋病毒新感染者中所占比例越来越大。 美国。目前使用的外用阴道杀菌剂， 壬醇-9(N-9)--一种以洗涤剂为基础的杀精剂 它的高避孕失败率还会导致粘膜侵蚀和 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 迫切需要杀菌剂来遏制艾滋病毒的阴道传播 感染。试图确定一种杀微生物剂避孕药 有可能预防艾滋病毒的性传播，以及 提供生育控制的一系列溴甲氧基取代新药 抗HIV药物齐多夫定(AZT；zidovudine)的衍生物 抗HIV和杀精双重活性的合成和检测 活动。两种先导化合物WHI-05和WHI-07显示出强大的抗癌活性。 艾滋病毒以及杀精活性。体内杀精效果观察 小鼠模型的有效性和局部毒性的缺乏表明 SHI-05和WHI-07作为双重功能将是有吸引力的候选者 阴道杀微生物剂。申请者现在提出了临床前研究 进一步评估这两种药物的临床潜力的研究 函数AZT衍生物。具体目标是：(I)评估在 WHI-05和WHI-07在兔体内的避孕活性； 评价WHI-05和WHI-07预防肠黏膜损伤的能力 猫科动物免疫缺陷病毒的围产期传播 自然寄主模型；(3)评估WHI-05和WHI-07的能力 为了防止HIV-1在黑猩猩体内的粘膜传播， 代理寄主模型；以及(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。双效阴道杀菌剂的研究进展 遏制艾滋病毒传播和预防生育将是一个重要的 挺身而出，保护性活跃女性免受阴道艾滋病毒感染 变速箱。WHI-05和WHI-05体内疗效的临床前数据 WHI-07将是进一步探索这些小说的用处所必需的 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.