On-Demand Pharmacological Contraception by Blocking ADCY 10

通过阻断 ADCY 10 进行按需药物避孕

• 批准号: 10017310
• 负责人: JOCHEN BUCK
• 金额: $ 198.26万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-12 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10017310
• 关键词: Acute; Adenylate Cyclase; Adverse effects; Andrology; Biochemical; Biochemistry; Catalytic Domain; Chemical Structure; Chemicals; Chronic; Computer Models; Contraceptive Agents; Contraceptive Usage; Contraceptive methods; Crystallization; Data; Development; Dose; Drug Design; Drug Kinetics; Ejaculation; Equilibrium; Exhibits; Female; Female Contraceptive Agents; Fertility; Genes; Genetic Recombination; Goals; Hour; Human; In Vitro; Injections; Institutes; Investigational Drugs; Knockout Mice; Laboratories; Lead; Male Contraceptive Agents; Methods; Mouse Strains; Mus; Oral; Oral Contraceptives; Partner in relationship; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phenotype; Physiology; Pregnancy; Process; Property; Protein Isoforms; Recording of previous events; Research; Safety; Series; Spectrum Analysis; Sperm Capacitation; Sterility; Structure; Testing; Therapeutic; Travel; analog; appropriate dose; base; design; drug development; drug structure; efficacy study; egg; expectation; experimental study; high throughput screening; improved; in vivo; inhibitor/antagonist; innovation; insight; male; male fertility; men; multidisciplinary; pill; preclinical development; preclinical evaluation; preclinical safety; prevent; prototype; reproductive tract; safety study; scaffold; side effect; small molecule; sperm cell; sperm function; structural biology; zygote

Overall Freshly ejaculated mammalian sperm are unable to fertilize an egg. They acquire fertilizing capacity in the hours following ejaculation, as they pass through the female reproductive tract, in a process known as capacitation. Soluble adenylyl cyclase (sAC: ADCY10) is a non-hormonal target essential for sperm capacitation and male fertility. Pharmacological sAC inhibitors block sperm functions in vitro and two distinct sAC knockout (KO) mouse strains exhibit male-specific sterility without exhibiting other overt phenotypes. This proposed Contraception Research Center (CRC) has a singular scientific theme; to identify the safest and most efficacious means for blocking sAC in vivo to achieve an on-demand contraceptive pill. The overall design of the CRC leverages the already successful interdisciplinary team comprised of expertise in sAC pharmacology and biochemistry (Drs. Levin & Buck), sAC structural biology (Dr. Steegborn), and medicinal chemistry and drug development [Dr. Meinke & his team at the Tri-Institutional Therapeutics Discovery Institute (TDI)]. To complete the CRC, we add to this team an Andrology Core (led by Drs. Lamb & Schlegel) for assessing efficacy against human sperm. In the first two Projects, we focus on sAC catalytic domain inhibitors with the expectation that pharmacokinetic parameters can be optimized to balance efficacy with minimal adverse effects. In the first project, we will perform in vivo studies of efficacy, safety, and pharmacokinetics to refine the existing scaffold of sAC inhibitors with proven efficacy in mice into preclinical development candidates suitable for development partners to apply for an FDA Investigational New Drug (IND). The goal of Project 2 is to develop additional leads, based upon recombination and optimization of moieties from distinct, but structurally and biochemically validated scaffolds, which would be suitable for subjecting to the in vivo studies proposed in Project 1. The third project proposes a high throughput screening strategy to identify inhibitors targeting regulatory domains of sAC isoforms enriched in sperm. Such inhibitors should exhibit diminished side effects. The ultimate goal of Project 3 is to identify hits which will be developed using the same principles and methods outlined in Projects 1 and 2. The overall hypothesis tested in this CRC is that sAC inhibitors can be designed which can be appropriately dosed to block sperm functions while minimizing undesirable side effects.

整体 哺乳动物新鲜射出的精子不能使卵子受精。他们获得了 射精后数小时内的能力，因为它们通过女性生殖道， 这个过程被称为获能。可溶性腺苷酸环化酶（sAC：ADCY 10）是一种非激素性的腺苷酸环化酶。 对精子获能和男性生育力至关重要的靶点。药理学sAC抑制剂阻断 精子在体外的功能和两个不同的sAC敲除（KO）小鼠品系表现出雄性特异性 不育而不表现出其他明显的表型。避孕研究中心 (CRC)有一个单一的科学主题;确定最安全和最有效的手段， 在体内阻断sAC以实现按需避孕药。铁路公司的整体设计 利用由sAC专业知识组成的已经成功的跨学科团队 药理学和生物化学（Levin & Buck博士），sAC结构生物学（Steegborn博士）， 药物化学和药物开发[Meinke博士和他的团队在三机构 Therapeutics Discovery Institute（TDI）。为了完成CRC，我们在此团队中添加了一个男科学 核心（由Lamb和Schlegel博士领导）用于评估对人类精子的有效性。前两 项目，我们专注于sAC催化结构域抑制剂，期望药代动力学 可以优化参数以平衡功效和最小的副作用。在第一个项目中， 我们将进行有效性、安全性和药代动力学的体内研究，以完善现有的 将在小鼠中已证实有效的sAC抑制剂支架转化为临床前开发候选药物 适合开发合作伙伴申请FDA研究性新药（IND）。目标 项目2的第一个目标是基于部分的重组和优化， 从不同的，但结构和生物化学验证的支架，这将是适合于 进行项目1中提出的体内研究。第三个项目提出了一个高 筛选靶向sAC亚型调节结构域的抑制剂的通量筛选策略 富含精子此类抑制剂应表现出减少的副作用。的最终目标 项目3是确定将使用所概述的相同原则和方法开发的命中 在项目1和2中。在本CRC中检验的总体假设是，sAC抑制剂可以 其设计可以适当地给药以阻断精子功能，同时最小化不期望的 副作用.