Vanadocenes as a New Class of Spermicidal Drugs

二茂钒作为一类新型杀精药物

• 批准号: 6644698
• 负责人: OSMOND J D'CRUZ
• 金额: $ 10万
• 依托单位: PARADIGM PHARMACEUTICALS, LLC
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-25 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6644698
• 关键词: cyclopentane; cytotoxicity; drug design /synthesis /production; emulsions; female antifertility drug; fertility; miniature swine; semen; spermicide; vanadium

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.

描述（由申请人提供）：基于洗涤剂的杀精子是美国最流行的可逆避孕剂形式，这些杀精子剂中的活性成分是非离子表面活性剂的nonoxynol-9（n-9），它以多种形式可用。表面活性剂的杀精子剂具有高避孕失败率，并干扰天然和保护性阴道机制，从而增强了性传播疾病传播和感染的风险。因此，需要提供改进的无毒性阴道杀菌剂。在系统的搜索工作中，识别潜在能够更好地性能并且没有洗涤剂型杀精子剂的弊端的非毒性杀剂剂，我们对几种二碱化金属衍生物进行了理性设计和合成，其中BIS（环丙烯基）部分将其定位在三位苯甲苯甲酸属性中，并在bis symetry intermetry and beconmentions中构成综合构成。我们发现钒（IV）或钒元的双（环戊二烯基）复合物具有快速，有效和选择性的精子活性。它们通过瞄准精子味剂的运动性 - 含膜毒性的运动能力，因此具有比当今可用的膜毒性更好。我们已经合成了一系列钒烯，并研究了简单无机钒盐的化学修饰如何改变钒的特性为有效的杀精子剂。与N-9不同，钒烯酸在纳摩尔到微摩尔范围是杀菌剂，对人类女性生殖道上皮细胞而没有细胞毒性，并且在动物模型中缺乏粘膜，全身性和生殖毒性。钒烯由于其有效的精子活性和缺乏炎症和毒性作用，因此可以用作女性的新型阴道避孕药。我们体外和体内研究的结果表明，含含二氧化二硫代氨基酸酯（VDDTC）的含含氧二世络合物（VDDTC）将是进一步作为阴道杀虫剂探索的有吸引力的候选者。因此，将进行临床前研究以测试相关动物模型中的体内避孕功效。发现猪模型是研究杀菌剂钒烯烯的体内避孕功效的合适动物模型。使用Minipig模型，我们将检验我们的假设，即在人工授精授精之前阴道传递了VDDTC的凝胶 - 微乳液配方将防止该概念而没有副作用。我们将测试VDDTC阴道施用的凝胶制剂的剂量和持续时间，该剂量在人为的和荷尔蒙底漆的镀金中生育速率。针对轻度避孕的基于机理的杀精子剂的发展将是避孕研究中的潜在范式转移区域。关于VDDTC凝胶制剂的体内疗效的临床前数据对于进一步探索VDDTC作为II期静脉内杀虫剂的实用性至关重要。