VANADOCENES AS A NEW CLASS OF SPERMICIDAL DRUGS

描述(申请人提供)：全世界迫切需要改进避孕措施，特别是预防性避孕措施。屏障避孕法是唯一一种保护使用者免受性传播疾病的避孕药。然而，目前可用的杀精避孕药效果不佳和/或有不良的毒性。为了系统地鉴定可能具有更好效果的无毒杀精剂，并且没有洗涤剂类杀精剂的缺点，我们合理地设计和合成了几个二取代茂金属衍生物。我们发现钒(IV)或钒多烯的双环戊二烯基络合物具有快速、有效和选择性的杀精活性。在第一阶段的资助下，我们展示了：(I)VDDTC通过凝胶微乳在兔和猪模型上的体内避孕活性；(Ii)证实VDDTC在小鼠、兔和猪模型中缺乏粘膜炎症潜能；(Iii)建立了一种与生理相关且敏感的猪阴道刺激模型；以及(Iv)发现VDDTC显著增强了抗逆转录病毒杀精剂WHI-07在猫免疫缺陷病毒/猫艾滋病模型中的杀微生物活性。在SBIR第二期的支持下，我们将扩大猪和兔模型的用途，以测试VDDTC的体内避孕效果、粘膜安全性以及发育毒性研究。我们将结合WHI-07进行VDDTC的有效性和安全性研究。我们推测，与单独使用VDDTC相比，这两种具有不同作用机制的活性药物的组合可能会改善双重保护的有效性和持续时间，同时保持足够的安全性。第二阶段研究的目标是(I)扩大VDDTC与VDDTC加WHI-07凝胶微乳体内避孕效果的猪模型的实用性；(Ii)通过表征细胞外、细胞、分子和组织学终点，扩大猪阴道刺激模型的实用性，用于VDDTC和VDDTC加WHI-07的临床前评估；以及(Iii)评估VDDTC对兔的发育毒性潜力。拟议的第二阶段工作将补充和加强Paradigm制药公司安全有效的预防性避孕药具的发现和临床前开发，这可能为预防艾滋病毒的性传播同时为妇女提供生育控制的新战略奠定基础。

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.