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

Award Number: R61HD099995
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = -$228,782 )
2023	2021	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Child Health and Human Development Extramural Research	000	2	3/21/2023	NON-COMPETING CONTINUATION	-$228,782
														Subtotal = -$228,782

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Child Health and Human Development Extramural Research	000	2	3/18/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $425,366 )
2021	2021	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Child Health and Human Development Extramural Research	000	2	3/19/2021	NON-COMPETING CONTINUATION	$425,366
														Subtotal = $425,366

Issue Date FY: 2020 ( Subtotal = $436,458 )
2020	2020	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Child Health and Human Development Extramural Research	000	1	4/6/2020	NEW	$436,458
														Subtotal = $436,458

Grand Total All Awards = $633,042

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

Award Number: R61HD099995

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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