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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：
10597164
负责人：
Feng Li
金额：
$ 55.53万
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/10597164
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 or chemical Tissue Distribution Epididymis Human Hydrogen Bonding 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 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 drug-like compound 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.

摘要