Assessing inhibitor efficacy in vivo and developing a biomarker for use during early phase clinical trials

评估抑制剂的体内功效并开发用于早期临床试验的生物标志物

• 批准号: 10747157
• 负责人: JOCHEN BUCK
• 金额: $ 60.16万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-10 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10747157
• 关键词: Acute; Adenylate Cyclase; Animal Model; Animals; Bicarbonates; Biological Markers; Cervical; Cervix Mucus; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; Collection; Contraceptive Agents; Contraceptive methods; Couples; Cyclic AMP; Data; Deposition; Development; Dose; Drug Design; Drug Kinetics; Drug Packaging; Ejaculation; Environment; Epididymis; Family Planning; Female; Fertilization; Fertilization in Vitro; Genetic; Goals; Hour; Human; In Vitro; Infertility; Injections; Investigational Drugs; Investigational New Drug Application; Knock-out; Lead; Male Contraceptive Agents; Mammalian Oviducts; Mediating; Medicine; Menstrual cycle; Methods; Mus; Oocytes; Oral; Oral Contraceptives; Oryctolagus cuniculus; Ovulation; Partner in relationship; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phenotype; Process; Property; Reflex action; Research; Research Project Grants; Rodent; Safety; Second Messenger Systems; Seminal fluid; Source; Sperm Motility; Spermatocytes; Sterility; Structure; Study models; Swimming; Testing; Time; Tissues; Toxicology; Translational Research; Travel; Uterus; Vagina; Woman; birth control; cell motility; contraceptive efficacy; drug candidate; drug development; early phase clinical trial; efficacy evaluation; experimental study; first-in-human; flexibility; in vivo; in vivo evaluation; inhibitor; innovation; knockout gene; lead candidate; loss of function; male; male fertility; men; new chemical entity; novel; pharmacodynamic biomarker; pharmacologic; pre-clinical; pre-clinical research; prevent; reproductive tract; residence; response; safety testing; sex; side effect; sperm cell

Project 2 Mammalian sperm are stored in the epididymis in a dormant state; they are immotile and unable to fertilize the oocyte. Upon ejaculation, motility is activated via bicarbonate-induced stimulation of soluble adenylyl cyclase (sAC: ADCY10). Men and male mice with the sAC gene knocked out are infertile, and pharmacological inhibitors specific for sAC block in vitro fertilization and render male mice temporarily infertile. Thus, sAC is a nonhormonal target, genetically and pharmacologically validated to be essential for male fertility. 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 this Contraception Translational Research Project, 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 goal of this Project, and the WCM-CRC, is to identify a lead candidate (along with backups) to progress into studies enabling an Investigational New Drug (IND) application as a novel oral, nonhormonal contraceptive for men.

项目2 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。 卵母细胞。射精时，运动通过碳酸氢盐诱导的可溶性腺苷酸的刺激而激活。 环酶(SAC：ADCY10)。带有SAC基因敲除的男性和雄性小鼠是不育的，而且 SAC特异性药物抑制体外受精并使雄性小鼠暂时受精 不孕不育。因此，SAC是一个非荷尔蒙靶标，从遗传学和药理学上都被证实是必不可少的。 为了男性生育能力。威尔康奈尔医学避孕研究中心(WCM-CRC)的目标是 将作用强烈的SAC抑制剂开发成安全有效的非激素、口服、按需提供的药物 避孕药，男性仅在性行为前不久根据需要和次数服用避孕药。在这种避孕方法中 翻译研究计划，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抑制剂的体内效果；并验证精子活力 一种用于按需男性早期临床试验的药效学生物标志物 避孕药。该项目和WCM-CRC的一个目标是确定一名主要候选人(以及 备份)以进入能够作为新型口服药物的研究性新药(IND)应用的研究， 男性非荷尔蒙避孕药。