On-demand nonhormonal male contraception via ADCY10 inhibition

总括 哺乳动物的精子储存在附睾处，处于休眠状态；它们不活动，不能受精。 鸡蛋。在射精时，精子开始游动，并启动一个称为获能的过程，在这个过程中，他们 有能力使卵母细胞受精。获能和运动激活的最初事件是 碳酸氢钠对可溶性腺苷环化酶(SAC：ADCY10)的刺激作用。男人和雄性老鼠带着 被敲除的SAC基因是不育的，在体内给雄性小鼠注射SAC抑制剂可以防止 精子的活力，并使雄性暂时不育。因此，从基因上讲，SAC是一个非荷尔蒙靶标。 在药理上被证实是男性生育所必需的。除了雄性特有的不育外，唯一的 SAC基因敲除者或小鼠的其他表型依赖于长期的SAC慢性丢失 一段时间。我们建议利用作用强烈的抑制剂，其效果将是暂时的，以避免 基于机制的副作用，并限制与长期服药相关的固有危险。的目标是 威尔·康奈尔医学避孕研究中心(WCM-CRC)将开发出有效的SAC 将抑制剂转化为安全有效的非荷尔蒙、口服、按需男性服用的避孕药 只有在需要的时候和频率，就在做爱前不久。在两个避孕药开发研究中 项目，我们建议提高结合亲和力、药代动力学(包括口服生物利用度)、类药物 SAC抑制剂的特征和安全性，预计药代动力学参数可以 优化以平衡疗效和最小的不良反应。在项目1中，我们关注的是一系列化学物质 在临床前动物模型中进行活体验证，在项目3中，我们建议开发更多的线索 从结构上不同的脚手架。在项目2中，我们将建立第二个非啮齿动物模型，用于 测试避孕效果；测试优化的SAC抑制剂的体内疗效；以及验证精子 运动性作为疗效的药效学生物标志物在按需临床试验中的应用 男性避孕药。WCM-CRC的主要目标是确定临床主要候选对象(以及 支持)进入研究性新药(IND)，使一种新的口服非激素药物能够进行研究 男性避孕药。

Overall Mammalian sperm are stored in the epididymis in a dormant state; they are immotile and unable to fertilize the egg. Upon ejaculation, sperm begin swimming and initiate a process called capacitation, where they become competent to fertilize the oocyte. An initial event in capacitation and activation of motility is the bicarbonate-induced stimulation of soluble adenylyl cyclase (sAC: ADCY10). Men and male mice with the sAC gene knocked out are infertile, and in vivo administration of sAC inhibitors to male mice prevents sperm motility and renders the males temporarily infertile. Thus, sAC is a nonhormonal target, genetically and pharmacologically validated to be essential for male fertility. Besides male-specific sterility, the only other phenotypes of sAC knockout men or mice are dependent upon chronic loss of sAC for extended periods of time. We propose to leverage acutely acting inhibitors, whose effects will be transient, to avoid mechanism-based side effects and limit the inherent perils associated with chronic dosing. The goal of the Weill Cornell Medicine Contraceptive Research Center (WCM-CRC) is to develop acutely acting sAC inhibitors into safe and effective nonhormonal, orally available, on-demand contraceptives which men take only when and as often as needed, shortly before sex. In two Contraceptive Development Research Projects, we propose to improve binding affinity, pharmacokinetics (including oral bioavailability), drug-like characteristics, and safety of sAC inhibitors with the expectation that pharmacokinetic parameters can be optimized to balance efficacy with minimal adverse effects. In Project 1, we focus on a chemical series validated in vivo in a preclinical animal model, and in Project 3, we propose to develop additional leads from structurally distinct scaffolds. In Project 2, we will establish a second, non-rodent animal model for testing contraceptive efficacy; test the in vivo efficacy of optimized sAC inhibitors; and validate sperm motility as a pharmacodynamic biomarker of efficacy for use in early phase clinical trials of an on-demand male contraceptive. A major goal of the WCM-CRC is to identify a clinical lead candidate (along with backups) to advance into Investigational New Drug (IND) enabling studies for a novel oral, nonhormonal contraceptive for men.