VANADOCENES AS A NEW CLASS OF SPERMICIDAL DRUGS

描述（由申请人提供）：全世界迫切需要改进的避孕药具，特别是预防性避孕药具。屏障避孕法是保护使用者免受性传播疾病侵害的唯一一类避孕药具。然而，目前可用的杀精子避孕药具有较差的功效和/或具有不期望的毒性。在一个系统的努力，以确定无毒杀精剂可能能够执行更好的，没有缺点的洗涤剂型杀精剂，我们已经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）或钒茂的双-二氢配合物具有快速、有效和选择性的杀精子活性。在第一阶段的资助下，我们证明了：（i）在兔和猪模型中通过凝胶-微乳液的VDDTC的体内避孕活性;（ii）在小鼠、兔和猪中证实了VDDTC缺乏粘膜炎症潜力;（iii）开发了生理相关和敏感的阴道刺激猪模型;和（iv）发现VDDTC显著增强抗逆转录病毒杀精剂WHI- 07在猫免疫缺陷病毒/猫AIDS模型中的杀微生物效力。在SBIR II期支持下，我们将扩大猪和兔模型的实用性，以测试VDDTC的体内避孕功效、粘膜安全性以及发育毒性研究。我们将进行VDDTC与WHI-07联合治疗的疗效和安全性研究。我们假设，与单独使用VDDTC相比，这两种具有不同作用机制的活性药物联合使用可能会改善双重保护的疗效和持续时间，同时保持足够的安全性。II期研究的目的是（i）扩大猪模型在VDDTC与VDDTC + WHI-07凝胶微乳体内避孕效力方面的实用性;（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在VDDTC和VDDTC + WHI-07临床前评价方面的实用性;以及（iii）评估VDDTC在家兔体内的发育毒性潜力。拟议的第二阶段工作将补充和加强Paradigm Pharmaceuticals安全有效的预防性避孕药的发现和临床前开发，这可能为预防艾滋病毒性传播的新战略提供基础，同时为妇女提供生育控制。

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.