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以休眠状态储存在附睾中；它们不动且无法受精鸡蛋。射精后，精子开始游动并启动一个称为获能的过程，在此过程中它们具有使卵母细胞受精的能力。获能和运动激活的初始事件是碳酸氢盐诱导的可溶性腺苷酸环化酶（sAC：ADCY10）的刺激。男性和雄性小鼠 sAC基因敲除导致不育，给雄性小鼠体内施用sAC抑制剂可以预防精子活力下降，导致雄性暂时不育。因此，sAC 是一个非激素靶点，从基因上来说并经药理学验证对男性生育能力至关重要。除了雄性不育之外，唯一 sAC 基因敲除的男性或小鼠的其他表型依赖于 sAC 长期丧失一段时间。我们建议利用作用剧烈的抑制剂，其作用是短暂的，以避免基于机制的副作用并限制与长期给药相关的固有危险。的目标威尔康奈尔医学避孕研究中心 (WCM-CRC) 将开发具有急性作用的 sAC 将抑制剂转化为男性服用的安全有效的非激素、口服、按需避孕药仅在需要时、在性行为前不久进行。两项避孕药具发展研究项目中，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）、类药性 sAC 抑制剂的特性和安全性，预计药代动力学参数可以优化以平衡功效与最小的副作用。在项目1中，我们专注于化学系列在临床前动物模型中进行了体内验证，在项目 3 中，我们建议开发额外的线索来自结构不同的支架。在项目2中，我们将建立第二种非啮齿类动物模型测试避孕效果；测试优化的 sAC 抑制剂的体内功效；并验证精子动力性作为药效生物标志物，用于按需药物的早期临床试验男性避孕药。 WCM-CRC 的一个主要目标是确定临床主要候选者（以及备份）以推进研究性新药（IND），从而能够研究一种新型口服非激素药物男性避孕药。