Optimization of lead candidates for an on-demand male contraceptive

按需男性避孕药主要候选药物的优化

基本信息

批准号：
10803570
负责人：
JOCHEN BUCK
金额：
$ 68.93万
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：
2023-09-21 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10803570
关键词：
Acrosome Reaction Acute Adenylate Cyclase Anatomy Animal Model Back Bicarbonates Binding Biological Assay Biological Availability Cervix Uteri Characteristics Chronic Circulation Contraceptive Agents Contraceptive methods Data Deposition Development Dose Drug Kinetics Ejaculation Epididymis Event Excretory function Female Fertilization in Vitro Gene Deletion Genetic Glaucoma Goals Half-Life Hour Human In Vitro Infertility Injections Investigational Drugs Investigational New Drug Application Investments Kidney Calculi Kinetics Knock-out Knockout Mice Lead Legal patent Male Contraceptive Agents Mammalian Oviducts Metabolism Metaphase Methods Molecular Mouse Strains Mus Mutation Oocytes Oral Oral Contraceptives Oryctolagus cuniculus Ovulation Partner in relationship Pathology Pharmaceutical Chemistry Pharmaceutical Preparations Phenotype Physiologic Intraocular Pressure Preclinical Testing Predisposition Process Property Proteins Research Contracts Resources Safety Series Sperm Capacitation Spermatocytes Sterility Swimming Testing Therapeutic Time Tissues Topical application Travel USAID Uterus Vagina Vaginal Ring absorption appropriate dose cell motility clinical development contraceptive efficacy design drug development drug standard efficacy study experimental study in vivo inhibitor innovation knockout gene lead candidate lead optimization male male fertility men novel pharmacologic pre-clinical preclinical development prevent reproductive tract residence side effect small molecule inhibitor sperm cell sperm function theories zygote

项目摘要

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. An initial event in capacitation and activation of motility is the HCO3- 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 temporarily render male mice infertile. Thus, sAC is a genetic and pharmacologically validated, non-hormonal target essential for male fertility. The overall hypothesis tested in this application is that sAC inhibitors can be designed which can be appropriately dosed to block sperm functions while minimizing undesirable side effects. We propose to test a series of potent, selective sAC inhibitors, using in vitro and in vivo studies of efficacy, safety, and pharmacokinetics, to identify the most well-developed, potent, selective, drug-like, non-toxic sAC inhibitors. The goal of this Project is to advance a compound from this series into preclinical development candidates suitable for development partners to apply for an FDA Investigational New Drug (IND) for a novel oral, non-hormonal contraceptive.

哺乳动物的精子储存在休眠状态的附睾中。他们是如果给鸡蛋施肥。射精后，精子开始游泳并启动一个称为的过程电容，在那里他们有能力施肥。电容和运动的激活是HCO3诱导的刺激可溶性腺苷酸环化酶（SAC：ADCY10）。男性和雄性小鼠被撞倒的囊基因是不育的，药理抑制剂针对SAC阻断体外受精，并暂时使雄性小鼠不育。因此，囊是遗传和药理验证的非荷尔蒙靶标对于男性生育必不可少的。这在此应用中测试的总体假设是可以设计SAC抑制剂适当地剂量阻断了精子功能，同时最大程度地减少了不良的副作用。我们建议使用体外和体内研究测试一系列有效的选择性SAC抑制剂疗效，安全性和药代动力学，以确定最发达，有效，选择性，类似药物的，无毒的SAC抑制剂。该项目的目的是从中推进一个化合物临床前开发候选人系列适用于开发伙伴申请 FDA研究新药（IND），用于一种新型的口服非激素避孕药。