Development of new ADCY10 inhibitors

计划2 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：ADCY10）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。在此测试中的总体假设 避孕研究中心（CRC）的研究表明，可以设计sAC抑制剂， 适当剂量以阻断精子功能，同时最小化不良副作用。在项目 1，我们开始对已经开发的一系列有效的选择性sAC抑制剂进行体内研究。 在这个避孕发展研究项目中，我们将根据 在不同的结构和生物化学验证的支架上。具体而言，我们将（1）设计 通过基于片段的药物设计（FBDD）和基于结构的药物设计的新化学系列 （2）使用sAC与各种抑制剂的可用共晶结构合成和 测试这些新化学结构的衍生物的小组;和（3）使用药物化学 和结构生物学来将化合物精制成具有改进的效力、选择性 和类似药物的性质。合适的替代sAC抑制剂将通过以下途径获得： 本CRC项目1中描述的优化周期和体内研究。这个项目的最终目标 该项目旨在开发sAC抑制剂作为口服非激素避孕药的先导化合物。

Project 2 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. The overall hypothesis tested in this Contraception Research Center (CRC) is that sAC inhibitors can be designed which can be appropriately dosed to block sperm functions while minimizing undesirable side effects. In Project 1, we embark on in vivo studies of an already developed series of potent, selective sAC inhibitors. In this Contraception Development Research Project, we will develop additional leads, based upon distinct structurally and biochemically validated scaffolds. Specifically, we will (1) design new chemical series by fragment-based drug design (FBDD) and structure-based drug design (SBDD) using available co-crystal structures of sAC with various inhibitors; (2) synthesize and test small panels of derivatives of these new chemical structures; and (3) use medicinal chemistry and structural biology to refine the compounds into inhibitors with improved potency, selectivity, and drug-like properties. Suitable alternative sAC inhibitors will be subjected to the pipeline of refinement cycles and in vivo studies described in Project 1 of this CRC. The ultimate goal of this Project is to develop sAC inhibitors as lead compounds for oral, non-hormonal contraceptives.