Optimization of in vivo validated ADCY10 inhibitors

体内验证的 ADCY10 抑制剂的优化

基本信息

批准号：
10747156
负责人：
LONNY R LEVIN
金额：
$ 39.56万
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/10747156
关键词：
Acute Adenylate Cyclase Affinity Animal Testing Bicarbonates Binding Biological Assay Biological Availability Biotechnology Cells Characteristics Chemicals Contraceptive Agents Contraceptive methods Cyclic AMP Data Development Dose Drug Design Drug Kinetics Ejaculation Enzymes Epididymis Exhibits Female Fertilization Fertilization in Vitro Funding Genetic Glaucoma Goals Hour Human In Vitro Infertility Injections Investigational New Drug Application Investments Kidney Calculi Kinetics Knock-out Knockout Mice Male Contraceptive Agents Male Infertility Mammalian Oviducts Mediating Medicine Metaphase Molecular Mouse Strains Mus Mutation Oocytes Oral Oral Contraceptives Oryctolagus cuniculus Ovulation Partner in relationship Pharmaceutical Preparations Pharmacologic Substance Phenotype Physiologic Intraocular Pressure Preclinical Testing Process Property Proteins Research Research Project Grants Resources Second Messenger Systems Series Source Sperm Motility Spermatocytes Sterility Structure Swimming Testing Tissues Topical application Travel USAID Vaginal Ring analog cell motility clinical development cross reactivity cytotoxicity design experimental study improved in vivo inhibitor lead optimization loss of function male male fertility member men middle age novel pharmacologic pill pre-clinical preclinical development prevent reproductive tract research and development research clinical testing residence response reversible contraceptive scaffold sex side effect sperm cell sperm function tool validation studies

项目摘要

Project 1 Sperm must be motile and complete capacitation to be able to fertilize the oocyte. Soluble adenylyl cyclase (sAC) is an enzyme in sperm that is essential for both processes. sAC knockout mice are male specific sterile, and men with mutations which disrupt sAC are infertile. In both mice and men, all other phenotypes observed require long periods of sAC absence to manifest. Thus, an acutely acting sAC inhibitor could be a safe and effective on-demand contraceptive by blocking sperm functions for hours without eliciting the side effects only seen when sAC is absent for months or years. Such a male birth control pill would only be taken when, and as often, as needed, shortly before sex. The goal of the Weill Cornell Medicine Contraception Research Center (WCM-CRC) is to develop acutely acting sAC inhibitors into on-demand birth control pills. This Contraception Development Research Project focuses on advancing the in vivo validated chemical series of sAC inhibitors which demonstrated proof-of-concept for on-demand male contraception in mice. A `tool' compound from this series renders male mice temporarily infertile. In this project, we propose lead optimization to enhance pharmacokinetic properties while maintaining (or improving) potency, drug-like properties, and other efficacy-defining features. The goal of these studies is a series of well-developed, potent, selective, drug-like, non-toxic, orally available sAC inhibitors with better pharmacokinetic profiles to progress into in vivo animal testing (Project 2 of the WCM-CRC). Our ultimate goal is to advance optimized leads into clinical development candidates suitable for an FDA Investigational New Drug (IND) application to test a novel oral, nonhormonal contraceptive for men.

项目1 精子必须是运动和完全的电容，才能施肥卵母细胞。可溶性腺苷酸环化酶（SAC）是精子中的一种酶，对这两个过程至关重要。 SAC敲除小鼠是男性特异的无菌的人和破坏囊突变的男性是不育的。在老鼠和男人中，所有其他表型观察到的需要长时间的SAC缺席才能表现出来。因此，敏锐的作用囊抑制剂可能是通过阻止精子功能几个小时而无需引起精子功能，一种安全有效的按需避孕药只有在缺少SAC几个月或数年时才能看到副作用。这样的男性避孕药只会在性爱前不久，在需要的情况下，按照需要进行。威尔·康奈尔医学的目标避孕研究中心（WCM-CRC）是将急性作用的SAC抑制剂发展为按需避孕药。这个避孕开发研究项目的重点是推进体内经过验证的化学系列SAC抑制剂，这些抑制剂证明了按需男性的概念验证小鼠的避孕。该系列的“工具”化合物使雄性小鼠暂时不育。在这个项目，我们建议铅优化以增强药代动力学特性，同时保持（或提高）效力，类似药物的特性和其他定义功效的特征。这些研究的目的是一系列发达的，有效的，选择性的，类似药物的，无毒的，口服的SAC抑制剂，具有更好的药代动力学特征以发展为体内动物测试（WCM-CRC的项目2）。我们的最终目标是将优化的铅提高到适合FDA研究的临床发展候选者新药（IND）应用于男性的新型口服，非激素避孕药。