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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.

哺乳动物的精子以休眠状态储存在附睾中；他们是不动的，无能的