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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.