On-demand nonhormonal male contraception via ADCY10 inhibition

通过 ADCY10 抑制按需非激素男性避孕

基本信息

批准号：
10747153
负责人：
JOCHEN BUCK
金额：
$ 199.95万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
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/10747153
关键词：
Acrosome Reaction Acute Adenylate Cyclase Adverse effects Affinity Animal Model Bicarbonates Binding Biochemistry Biological Availability Biology Biotechnology Cervix Uteri Characteristics Chemicals Chronic Clinical Complement Contraceptive Agents Contraceptive methods Data Deposition Dose Drug Design Drug Kinetics Ejaculation Epididymis Equilibrium Event Fertility Fertilization in Vitro Gene Deletion Glaucoma Goals Human Infertility Investigational Drugs Investigational New Drug Application Investments Kidney Calculi Kinetics Knock-out Knockout Mice Male Contraceptive Agents Mammalian Oviducts Measures Medicine Methodology Methods Molecular Mouse Strains Mus Mutation Oocytes Oral Oral Contraceptives Oryctolagus cuniculus Ovulation Partner in relationship Pharmaceutical Preparations Pharmacologic Substance Pharmacology Phase Phenotype Physiologic Intraocular Pressure Physiology Process Property Research Research Contracts Research Project Grants Resources Safety Series Sperm Motility Spermatocytes Sterility Structure Swimming Testing Therapeutic Time Tissues Topical application Travel USAID Uterus Vagina Vaginal Ring Validation Woman Work cell motility clinical development contraceptive efficacy design drug development drug discovery early phase clinical trial expectation experimental study improved in vivo in vivo evaluation inhibitor innovation knockout gene lead candidate male male fertility men multidisciplinary novel pharmacodynamic biomarker pharmacologic pre-clinical preclinical study prevent research and development scaffold sex side effect small molecule inhibitor sperm cell sperm function structural biology success zygote

项目摘要

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.

全面的哺乳动物的精子储存在休眠状态的附睾中。他们是如果immotile，无法施肥鸡蛋。射精后，精子开始游泳并启动一个称为电容的过程有能力施肥卵母细胞。运动和激活运动的初始事件是碳酸氢盐诱导的可溶性腺苷酸环化酶的刺激（SAC：ADCY10）。男性和雄性老鼠撞倒的囊基因是不育的，在体内给予雄性小鼠的囊囊抑制剂可防止精子运动并使男性暂时不育。因此，SAC是一个非激素靶标，在遗传上并在药理学上证明是男性生育至关重要的。除了男性特异性的无菌性，唯一 SAC基因敲除或小鼠的其他表型取决于延长的慢性SAC的慢性损失一段时间。我们建议利用敏锐的作用抑制剂，其影响将是短暂的，以避免基于机制的副作用并限制与慢性剂量相关的固有危险。目标的目标 Weill Cornell Medicine避孕研究中心（WCM-CRC）是开发敏锐的表演囊男人服用的抑制剂成安全有效的非激素，口服的按需避孕药只有在性行为之前和频繁的频率。在两项避孕开发研究中项目，我们建议改善结合亲和力，药代动力学（包括口服生物利用度），类似药物 SAC抑制剂的特性和安全性，预期药代动力学参数可以是优化以平衡功效与最小的不利影响。在项目1中，我们专注于化学系列在临床前动物模型中经过验证的体内验证，在项目3中，我们建议开发其他潜在客户来自结构上不同的支架。在项目2中，我们将建立第二种非旋转动物模型测试避孕功效；测试优化的SAC抑制剂的体内功效；并验证精子运动性作为在按需的早期临床试验中使用的药效学生物标志物男性避孕。 WCM-CRC的主要目标是确定临床主要候选人（以及备份）促进研究新药物（IND），以实现新的口服，非激素的研究男人的避孕。