Vanadocenes as a New Class of Spermicidal Drugs

描述(申请人提供)：以洗涤剂为基础的杀精剂是美国最受欢迎的可逆避孕形式。这些杀精剂的有效成分是非离子表面活性剂--壬氧醇-9(N-9)，已有30多年的历史。表面活性杀精剂具有很高的避孕失败率，并干扰自然和保护阴道的机制，从而增加传播和性传播疾病感染的风险。因此，提供改进的无毒性的阴道杀精剂是可取的。为了系统地寻找能够起到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，其中双(环戊二烯)基团相对于中心过渡金属原子处于四面体对称和弯曲构象。我们发现双(环戊二烯基)钒(IV)或钒多烯类化合物具有快速、有效和选择性的杀精活性。它们通过靶向精子的运动装置发挥作用--钒多烯类化合物没有膜毒性，因此比目前可用的有可能表现得更好。我们合成了一系列的钒并研究了简单的无机钒盐的化学修饰如何改变钒作为高效杀精剂的性质。与N-9不同，香草烯在纳摩尔到微摩尔范围内具有杀精作用，对人类女性生殖道上皮细胞没有细胞毒性，在动物模型中也没有粘膜、全身和生殖毒性。由于具有较强的杀精活性，且无炎症和毒性作用，因此可能成为一类新的女性阴道避孕药。我们的体外和体内研究结果表明，钒并二硫代氨基甲酸酯(VDDTC)是一种很有吸引力的阴道杀精剂。因此，将进行临床前研究，在相关动物模型中测试体内避孕效果。猪模型是研究杀精香草烯体内避孕效果的合适动物模型。使用小型猪模型，我们将检验我们的假设，即人工授精前经阴道注射VDDTC凝胶微乳剂将阻止受孕，而不会产生副作用。我们将测试阴道应用VDDTC凝胶制剂的剂量和持续时间对人工授精和激素引发的小母猪受精率的影响。针对温和避孕的基于机制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。有关VDDTC凝胶制剂体内有效性的临床前数据将为进一步探索VDDTC作为阴道内杀精剂在II期的应用奠定基础。

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.