NOVEL CONTRACEPTIVES WITH ANTI-HIV ACTIVITY

具有抗艾滋病毒活性的新型避孕药

• 批准号: 2799089
• 负责人: OSMOND J D'CRUZ
• 金额: $ 23.85万
• 依托单位: PARKER HUGHES INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-15 至 2001-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2799089
• 关键词: HIV infections; Pan; antiAIDS agent; cats; contraceptives; disease /disorder model; drug adverse effect; drug screening /evaluation; feline immunodeficiency virus; human immunodeficiency virus 1; laboratory mouse; laboratory rabbit; pharmacokinetics; spermicide; zidovudine

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.

描述：（改编自申请人的摘要） 人类免疫缺陷病毒（HIV），艾滋病的病因是 生殖年龄妇女中生长最快的死亡原因。 异性传播占所有艾滋病毒感染的80％世界 - 广泛，构成了越来越多的新艾滋病毒感染 美国。当前使用的局部阴道杀菌剂， 非氧合诺酚-9（N-9）-A基于洗涤剂的杀病毒杀菌剂。 其高避孕失败率也会导致粘膜侵蚀和 局部炎症，可能会增加艾滋病毒传播的风险。 因此，新的，有效，安全和女性控制的阴道 迫切需要微质抑制艾滋病毒的阴道传播 感染。试图识别杀菌剂避孕药 有可能防止艾滋病毒的性传播以及 提供生育控制，一系列Bromo-甲氧不是替代的小说 抗HIV药物的衍生物，氮氨酸氨基氨酸（AZT； Zidovudine）为 合成并检查了双重抗HIV活性和精子剂 活动。两种铅化合物WHI-05和WHI-07表现出有效的抗 HIV以及精子活性。体内精子的结果 小鼠模型中的功效和缺乏局部毒性表明 SHI-05和WHI-07将作为双重功能有吸引力的候选人 阴道微生物。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。具体目的是：（i）评估 兔子中WHI-05和WHI-07的体内避孕活动； （ii）到 评估WHI-05和WHI-07的能力防止透射和 猫免疫缺陷病毒在猫中的围产期传播作为 天然宿主模型； （iii）评估WHI-05和WHI-07的能力 为了防止黑猩猩在黑猩猩中的传播传播作为一个 替代主机模型； （iv）进行体内发育， WHI-05和WHI-07的生殖毒理学以及癌变研究 在啮齿动物模型中。双重功能阴道微生物的发展 遏制艾滋病毒的传播和防止生育能力将是重要的 向前迈进，保护性活跃的女性免受阴道艾滋病毒的侵害 传播。 WHI-05和 whi-07对于进一步探索这些小说的实用性至关重要 人类患者临床研究的药物。