Vanadocenes as a New Class of Spermicidal Drugs

描述（由申请人提供）：在美国，基于洗涤剂的杀精子剂是最流行的可逆避孕形式，这些杀精子剂中的活性成分是壬苯醇醚-9（N-9），一种非离子表面活性剂，已以各种形式提供超过30年。表面活性剂杀精剂具有较高的避孕失败率，并干扰自然和保护性阴道机制，从而增加了性传播疾病传播和感染的风险。因此，希望提供改进的无毒性的阴道杀精子剂。在一个系统的搜索努力，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的茂金属衍生物，其中双（双）部分位于四面体对称和弯曲的构象相对于中心过渡金属原子。我们发现钒（IV）或钒茂的双（III）配合物具有快速、有效和选择性的杀精子活性。它们通过靶向精子的运动器官而起作用，钒茂没有膜毒性，因此有可能比今天的那些表现得更好。我们合成了一系列二茂钒化合物，并研究了简单无机钒盐的化学修饰如何改变钒作为有效杀精子剂的性质。与N-9不同，钒茂在纳摩尔至微摩尔范围内具有杀精子作用，对人类女性生殖道上皮细胞没有细胞毒性，并且在动物模型中没有粘膜、全身和生殖毒性。钒茂类化合物，由于其有效的杀精子活性和缺乏炎症和毒性作用，可能是有用的一类新的阴道避孕药的妇女。我们的体外和体内研究结果表明，铅钒茂络合物，二硫代氨基甲酸钒茂（VDDTC），将是一个有吸引力的候选人，进一步探索作为阴道杀精剂。因此，将进行临床前研究，以在相关动物模型中检测体内避孕功效。猪模型被认为是一个合适的动物模型，用于研究杀精子的钒茂化合物的体内避孕效果。使用小型猪模型，我们将测试我们的假设，即在人工授精之前阴道递送的VDDTC凝胶-微乳液制剂将防止受孕而没有副作用。我们将检测阴道应用VDDTC凝胶制剂的剂量和持续时间对人工授精和经阴道预处理后备母猪生育率的影响。以温和避孕为目的的机制为基础的杀精剂的开发将是避孕研究中一个潜在的范式转变领域。关于VDDTC凝胶制剂的体内功效的临床前数据对于进一步探索VDDTC作为阴道内杀精剂在II期中的效用将是至关重要的。

DESCRIPTION (provided by applicant): Detergent-based spermicides are the most popular forms of reversible contraception in the United States the active ingredient in these spermicides is nonoxynol-9 (N-9), a non-ionic surfactant, which has been available in various forms for over 30 years. Surfactant spermicides have high contraceptive failure rate and interfere with natural and protective vaginal mechanisms thereby enhancing the risk of transmission and infection by a sexually transmitted disease. It would be desirable, therefore, to provide improved vaginal spermicides without toxicity. In a systematic search effort to identify non-toxic spermicides potentially capable of performing better and without the drawback of detergent-type spermicides, we have rationally designed and synthesized several disubstituted metallocene derivatives, where bis(cyclopentadienyl) moieties are positioned in a tetrahedral symmetry and in a bent conformation with respect to the central transition metal atoms. We discovered bis (cyclopentadienyl) complexes of vanadium(IV) or vanadocenes to have rapid, potent, and selective spermicidal activity. They work by targeting the motility-apparatus of sperm Vanadocenes lack membrane toxicity and hence have the potential to perform better, than those available today. We have synthesized a series of vanadocenes and studied how chemical modification of simple inorganic vanadium salt alters the properties of vanadium as potent spermicides. Unlike N-9, vanadocenes are spermicidal at nanomolar to micromolar ranges without cytotoxicity to human female genital tract epithelial cells and lack mucosal, systemic, and reproductive toxicity in animal models. Vanadocenes, because of their potent spermicidal activity and lack of inflammatory and toxic effects, may be useful as a new class of vaginal contraceptives for women. Results of our in vitro and in vivo studies indicated that the lead vanadocene complex, vanadocene dithiocatbamate (VDDTC), would be an attractive candidate to further explore as a vaginal spermicide. Therefore, preclinical studies will be performed to test the in vivo contraceptive efficacy in the relevant animal model. The porcine model was found to be a suitable animal model for investigating the in vivo contraceptive efficacy of spermicidal vanadocenes. Using the minipig model, we will test our hypothesis that vaginally delivered gel-microemulsion formulation of VDDTC prior to artificial insemination will prevent the conception without side effects. We will test the dose and duration of vaginally applied gel formulation of VDDTC on fertility rates in artificially inseminated and hormonally primed gilts. The development of a mechanism-based spermicide aimed at mild contraception will be a potentially paradigm shifting area in contraception research. The preclinical data on the in vivo efficacy of gel formulation of VDDTC will be essential to further explore the utility of VDDTC as an intravaginal spermicide in Phase II.