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

• 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
• 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

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.

摘要 开发一种小分子男性避孕药是复杂的血睾丸屏障（BTB）和血-睾丸屏障。 附睾屏障（BEB），因为许多男性避孕目标定位于附睾的近腔室， 生精上皮或附睾管腔内的精子。更好地了解 赋予异生物质穿过BTB或BEB的能力的化学特征将有助于发现和 开发新的男性避孕药。已发表的数据和我们对新型睾丸溴结构域（BRDT）的研究 抑制剂表明有可能鉴定促进穿过BTB或BEB的特性。我们将 确定促进药物在两个单独的R61中通过BTB和BEB的关键化学特征 和R33相。在R61阶段，我们将1）优化用于测量小鼠的方案和通量 使用药物测试集测量组织分布;以及2）测量100种化合物及其组合的组织分布。 代谢物，并确定影响睾丸传递的分子描述符。我们将用化学方法 小鼠血浆、睾丸网液（RTF）、睾丸和附睾中的不相关化合物，使用液体 色谱-质谱法（LC-MS）。睾丸网、睾丸和睾丸中的复合空间分布 附睾将使用成像MS进行映射。我们将使用化学信息学来关联结构， 使用实验RTF/血浆、睾丸/血浆和附睾/血浆比率的分子描述符， 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 了解并直接测试改变关键推断的物理性质或分子的影响， 描述符我们将3）使用一系列合理设计的合成方法来验证所识别的化学特征。 类似物分析化合物系列将使我们能够区分物理化学参数的趋势 以及由特定化学型赋予的特殊性质。我们还将测试另外200种新颖的小型 分子以鉴定影响睾丸摄取的新化学型，以及5）测试其摄取 使用转运蛋白敲除小鼠来确定组织分布， 在没有转运蛋白的情况下发生，以改善我们对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之后起作用的药物的预测吸收规则， 新的男性避孕药和治疗药物的鉴定， 睾丸或附睾的特殊区室将是有益的。