Elucidating Chemical Features that Block or Facilitate Passage across the Blood-Testis and/or Blood-Epidydimal Barriers in Mice

阐明阻止或促进小鼠血睾丸和/或血附睾屏障通过的化学特征

基本信息

批准号：
10577984
负责人：
Feng Li
金额：
$ 55.8万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-06 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10577984
关键词：
Address Affect Anti-Retroviral Agents Antidepressive Agents Area Binding Proteins Biological Assay Blood Blood-Testis Barrier Bromodomain Chemical Structure Chemicals Complement Contraceptive Agents Contraceptive methods Data Descriptor Development Diffusion Drug Design Drug or chemical Tissue Distribution Epididymis Human Hydrogen Bonding Image Immune Infection Informatics Knock-out Knockout Mice Liquid substance Male Contraceptive Agents Male Genital Organs Malignant Neoplasms Maps Mass Spectrum Analysis Measures Mediating Medical Membrane Methods Modeling Modification Molecular Molecular Structure Mus National Institute of Child Health and Human Development Natural Product Drug Natural Products Permeability Pharmaceutical Preparations Phase Piperazines Plasma Plasma Proteins Population Growth Positioning Attribute Property Protocols documentation Publishing Series Spatial Distribution Structure Testing Testis Therapeutic Variant Wild Type Mouse Work Xenobiotics analog contraceptive target drug discovery drug market drug testing improved inhibitor insight lipid solubility liquid chromatography mass spectrometry mass spectrometric imaging men mouse model novel physical property prevent public health relevance rational design reproductive tract scaffold small molecule sperm cell spermatogenic epithelium structure trend unintended pregnancy uptake

项目摘要

ABSTRACT Developing a small molecule male contraceptive is complicated by the blood-testis barrier (BTB) and blood- epididymal barrier (BEB), since many male contraceptive targets are localized to the adluminal compartment of the seminiferous epithelium or to sperm within the epididymal tubule lumen. Improved understanding of the chemical features that confer the ability for xenobiotics to cross BTB or BEB will facilitate the discovery and development of new male contraceptives. Published data and our studies of novel bromodomain testis (BRDT) inhibitors suggest that it is possible to identify properties that facilitate passage across the BTB or BEB. We will identify key chemical features that facilitate the passage of drugs across BTB and BEB in two separate R61 and R33 phases. In the R61 phase, we will 1) optimize the protocols and throughput for measuring mouse tissue distribution using a drug test set; and 2) measure tissue distribution of 100 compounds and their metabolites and identify molecular descriptors that influence delivery to the testis. We will quantify chemically unrelated compounds in mouse plasma, rete testis fluid (RTF), testis, and epididymis using liquid chromatography mass spectrometry (LC-MS). Compound spatial distribution in the rete testis, testis, and epididymis will be mapped using imaging MS. We will use chemoinformatics to correlate structures and molecular descriptors with the experimental RTF/plasma, testis/plasma, and epididymis/plasma ratios to identify features that facilitate or impede testis accumulation. In the R33 phase we plan to broaden our understanding and directly test the effects of altering the key inferred physical properties or molecular descriptors. We will 3) validate identified chemical features using a series of rationally designed synthetic analogs. Analyzing compound series will allow us to distinguish between trends in physicochemical parameters and special properties conferred by a particular chemotype. We will 4) test an additional 200 novel small molecules to identify new chemotypes that influence testis uptake and 5) test outlier compounds whose uptake belies their physical properties using transporter knock-out mice, to determine the tissue distribution that occurs without transporters so as to improve our physicochemical permeability models for the BTB and BEB. This work will establish predictive uptake rules applicable to drugs that must act behind BTB or BEB, facilitating the identification of new male contraceptives and of therapeutics for which accumulation in the immune- privileged compartments of the testis or epididymis would be beneficial.

抽象的血睾屏障 (BTB) 和血睾屏障使小分子男性避孕药的开发变得复杂。附睾屏障（BEB），因为许多男性避孕目标位于附睾的腔内室生精上皮或附睾管腔内的精子。增进了对赋予外源物交叉 BTB 或 BEB 能力的化学特征将有助于发现和开发新型男性避孕药。已发表的数据和我们对新型溴结构域睾丸 (BRDT) 的研究抑制剂表明有可能确定促进穿过 BTB 或 BEB 的特性。我们将确定促进药物在两个单独的 R61 中穿过 BTB 和 BEB 的关键化学特征和R33相。在R61阶段，我们将1）优化测量鼠标的协议和吞吐量使用药物测试装置进行组织分布； 2) 测量 100 种化合物及其组织分布代谢物并识别影响睾丸输送的分子描述符。我们将进行化学定量使用液体检测小鼠血浆、睾丸网液 (RTF)、睾丸和附睾中的无关化合物色谱质谱法（LC-MS）。睾丸网、睾丸和睾丸的复合空间分布将使用成像 MS 绘制附睾图。我们将使用化学信息学来关联结构和分子描述符与实验 RTF/血浆、睾丸/血浆和附睾/血浆比率识别促进或阻碍睾丸积聚的特征。在 R33 阶段，我们计划扩大我们的范围了解并直接测试改变关键推断物理特性或分子的影响描述符。我们将 3) 使用一系列合理设计的合成材料来验证已识别的化学特征类似物。分析化合物系列将使我们能够区分理化参数的趋势以及特定化学型赋予的特殊特性。我们将4）测试另外200个小说小分子来识别影响睾丸摄取的新化学型，以及 5) 测试其摄取的异常化合物使用转运蛋白敲除小鼠掩盖其物理特性，以确定其组织分布在没有转运蛋白的情况下发生，以改进我们的 BTB 和 BEB 的物理化学渗透性模型。这项工作将建立适用于必须在 BTB 或 BEB 后面起作用的药物的预测摄取规则，促进确定新的男性避孕药和治疗方法，以使其在免疫系统中积累睾丸或附睾的特殊隔室将是有益的。