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

> **NIH NIH R33** · BAYLOR COLLEGE OF MEDICINE · 2022 · $558,042

## Abstract

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.

## Key facts

- **NIH application ID:** 10577984
- **Project number:** 4R33HD099995-03
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Feng Li
- **Activity code:** R33 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $558,042
- **Award type:** 4N
- **Project period:** 2020-04-06 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10577984

## Citation

> US National Institutes of Health, RePORTER application 10577984, Elucidating Chemical Features that Block or Facilitate Passage across the Blood-Testis and/or Blood-Epidydimal Barriers in Mice (4R33HD099995-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10577984. Licensed CC0.

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