(P-208) Identifying Chemical Features that Favor or Block the Passage across the Blood-Testis Barrier in Mice

Abstract Authors: Qin Xin¹; John M. Hakenjos¹; Jian Wang¹; Zhi Tan^1,2; Kevin R. MacKenzie^1,2; Martin M. Matzuk^1,2; Feng Li^1,2

1. Center for Drug Discovery; Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA

2. NMR and Drug Metabolism Core, Advanced Technology Cores, Baylor College of Medicine, Houston, TX, USA

3. Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, TX, USA

Abstract Text: Understanding the chemical features that influence the ability for xenobiotics to cross the blood-testis barrier (BTB) will facilitate the discovery and development of new male contraceptives since many male contraceptive targets are localized to the adluminal compartment of the seminiferous epithelium. We identified key chemical features that facilitate or block the passage of drugs across the BTB by measuring tissue distribution of a total of 300 compounds and their major metabolites using liquid chromatography mass spectrometry (LC-MS) and inferring the properties that influence accumulation in the male genital tract. We have also determined if a compound passes the BTB by monitoring its spatial distribution in the testis using imaging mass spectrometry. Our tissue distribution data indicate that compounds containing N-dialkyl-, N-monoalkyl-, naphthol-, and biphenyl- chemotypes facilitate mouse testis uptake and accumulation. Conversely, compounds bearing carboxylic acid, glucuronic acid, nitrogen oxide, phenol or primary alcohol oppose testis uptake and compound accumulation in the testis. We are using cheminformatics to correlate structures and molecular descriptors with the experimental tissue distribution data to identify features that facilitate or impede testis accumulation, and we are employing these data to develop explainable Machine Learning to predict drug accumulation in testis. Overall, this work will establish predictive uptake rules applicable to drugs that must act behind BTB, which facilitate the development of new male contraceptives for which accumulation in the testis.

This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (R61/R33HD099995) to Feng Li; R01 HD110038 to Dr. Martin. M. Matzuk.