VANADOCENES AS A NEW CLASS OF SPERMICIDAL DRUGS

Vanadocenes 作为一类新的杀精药物

• 批准号: 7107612
• 负责人: OSMOND J D'CRUZ
• 金额: $ 29.39万
• 依托单位: PARADIGM PHARMACEUTICALS, LLC
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7107612
• 关键词: antiAIDS agent; antiinfective agents; cytokine; digital imaging; drug design /synthesis /production; embryo /fetus toxicology; emulsions; female; flow cytometry; gel; histopathology; immunocytochemistry; inflammation; irritation /irritant; laboratory rabbit; metal complex; mucosa; reproductive system pharmacology; sexually transmitted diseases; spermicide; swine; thiocarbamate; topical drug application; vanadium; women' s health; zidovudine

DESCRIPTION (provided by applicant): There is an urgent need, worldwide, for improved contraceptives, especially prophylactic contraceptives. Barrier methods are the only class of contraceptives that protects users against sexually transmitted diseases. However, currently available spermicidal contraceptives suffer from poor efficacy and/or have undesirable toxicity. In a systematic effort to identify non-toxic spermicides potentially capable of performing better and without the drawbacks of detergent-type spermicides, we have rationally designed and synthesized several disubstituted metallocene derivatives. We discovered bis-cyclopentadienyl complexes of vanadium(IV) or vanadocenes to have rapid, potent, and selective spermicidal activity. Under Phase I funding, we demonstrated: (i) in vivo contraceptive activity of VDDTC via a gel-microemulsion in rabbits and porcine models; (ii) confirmed the lack of mucosal inflammatory potential of VDDTC in mice, rabbits, and pigs; (iii) developed a physiologically relevant and sensitive porcine model for vaginal irritation; and (iv) discovered that VDDTC significantly enhanced the microbicide efficacy of the antiretroviral spermicide WHI- 07 in the feline immunodeficiency virus/cat model of AIDS. Under SBIR Phase II support, we will expand the utility of the porcine and rabbit models to test the in vivo contraceptive efficacy, mucosal safety as well as developmental toxicity studies of VDDTC. We will perform these efficacy and safety studies of VDDTC in combination with WHI-07. We hypothesize that the combination of these two active agents with different mechanisms of action will potentially improve efficacy and duration of dual-protection when compared with VDDTC alone while maintaining an adequate safety profile. The goals of Phase II study are (i) to expand the utility of porcine model for the in vivo contraceptive efficacy of VDDTC versus VDDTC plus WHI-07 gel microemulsion; (ii) to expand the utility of porcine vaginal irritation model for the preclinical evaluation of VDDTC and VDDTC plus WHI-07 by characterizing the extracellular, cellular, molecular and histological endpoints; and (iii) to assess the developmental toxicity potential of VDDTC in rabbits. The proposed Phase II work will complement and enhance the discovery and preclinical development of safe and effective prophylactic contraceptives at Paradigm Pharmaceuticals that may provide the basis for a new strategy to prevent the sexual transmission of HIV while providing fertility control for women.

描述（由申请人提供）：在全球范围内，迫切需要改进的避孕药具，尤其是预防性避孕药。障碍方法是保护用户免受性传播疾病的唯一类别。但是，目前可用的精子避孕药遭受功效不佳和/或不良毒性。为了系统地识别潜在能够更好地执行和没有去污剂型杀精子剂的缺点的无毒杀精子剂，我们对几种脱叠奠定的金属世衍生物进行了理性设计和合成。我们发现了钒（IV）或钒烯的双囊二烯基络合物具有快速，有效和选择性的精子活性。在第一阶段的资金下，我们证明了：（i）VDDTC通过兔和猪模型中VDDTC的体内避孕活动； （ii）证实了VDDTC在小鼠，兔子和猪中缺乏粘膜炎症潜力； （iii）开发了一种与阴道刺激的生理相关和敏感的猪模型； （iv）发现，VDDTC在猫免疫缺陷病毒/艾滋病模型中显着增强了抗逆转录病毒杀菌剂的杀菌剂疗效。在SBIR II期支持下，我们将扩大猪和兔模型的实用性，以测试体内避孕功效，粘膜安全性以及VDDTC的发育毒性研究。我们将与WHI-07结合使用VDDTC的这些功效和安全性研究。我们假设这两种活性药物与不同的作用机制的组合将有可能提高双重保护的疗效和单独的VDDTC，同时保持足够的安全性。第二阶段研究的目标是（i）扩展猪模型对VDDTC与VDDTC的体内避孕功效的实用性，以及VDDTC加上WHI-07凝胶微乳液； （ii）通过表征细胞外，细胞，分子和组织学终点的表征，扩大了VDDTC和VDDTC Plus WHI-07的临床前评估的猪阴道刺激模型的实用性； （iii）评估VDDTC在兔子中的发育毒性潜力。拟议的第二阶段工作将补充和增强在范式药物的安全有效预防性避孕药的发现和临床前开发，这些避孕药可以为防止艾滋病毒的性传播提供新策略的基础，同时为妇女提供生育能力。