The long-term goal of this research is to improve our understanding of thyroid hormone action using ligand- based, small molecule approaches. Thyroid hormone has important actions related to health and disease in all tissues of the body including the central nervous system (CNS) where thyroid hormone plays a key role in regulating brain development and maintaining specialized cell populations and structures such as myelin. Compared to thyroid hormone's actions in the periphery, much less is known at the molecular and mechanistic level about its actions in the brain, and increased knowledge of thyroid hormone brain actions would be useful for developing new therapeutics for CNS disorders that intersect with thyroid hormone action including multiple sclerosis and other demyelinating diseases, and Allan-Herndon-Dudley Syndrome and other disorders involving unbalanced thyroid hormone levels in the CNS. A major limitation from a ligand/small molecule perspective is that there are currently no thyroid hormone receptor (TR) ligands, endogenous or synthetic, that distribute preferentially to the CNS from a systemically administered dose. As such, it is difficult to separate CNS from peripheral hormone effects and the lack of a therapeutic window separating desired therapeutic CNS actions from undesired systemic toxic actions is emblematic of this issue. The proposed research plan seeks to address this problem by devising and validating a pro-drug based strategy that will selectively deliver a TR ligand across the blood-brain-barrier (BBB) and into the CNS while minimizing the TR ligand exposure in circulation and peripheral organs and tissues. This selective increase in CNS vs. peripheral exposure should result in an increased window separating TR driven CNS effects from those in the periphery. The pro-drug design is based on amino-ester derivatives of TR ligands and these novel compounds will be synthesized and evaluated for CNS uptake in Specific Aim 1. CNS-selective TR activation will be assayed in Specific Aim 2 through a series of functional assays involving TR in the CNS and periphery.
In Specific Aim 3, the mechanism of BBB penetration, pro-drug activation, pro-drug pharmacokinetics, and pro-drug influence on free drug in the CNS will be evaluated. This research will enable the creation of new CNS-selective TR ligands that will be useful as research tools and potentially serve as prototypes for new thyroid hormone-based therapeutics for CNS disorders.

Public Health Relevance

This research seeks to design, synthesize, and characterize novel thyroid hormone receptor (TR) ligands that have selective actions in the central nervous system (CNS). There are several CNS disorders that might benefit from stimulation of thyroid hormone signaling pathways, but most if not all of the known TR ligands do not possess the necessary safety margin separating the stimulation of desired thyroid action in the CNS from undesired actions in non-CNS tissues. Our approach involves the development of a pro-drug strategy that masks the TR ligand making it inactive in blood and non-CNS tissue. However, upon accessing the CNS by penetration of the blood-brain-barrier, the pro-drug protection is unmasked revealing the active TR ligand. The purpose of this research is to test and validate this approach to generate new thyroid hormone based research tools and drugs for use in the CNS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK052798-21
Application #
9857010
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Silva, Corinne M
Project Start
1997-09-30
Project End
2020-12-31
Budget Start
2020-01-01
Budget End
2020-12-31
Support Year
21
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
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Devereaux, Jordan; Ferrara, Skylar J; Scanlan, Thomas S (2018) Quantification of Thyromimetic Sobetirome Concentration in Biological Tissue Samples. Methods Mol Biol 1801:193-206
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Ferrara, Skylar J; Meinig, J Matthew; Placzek, Andrew T et al. (2017) Ester-to-amide rearrangement of ethanolamine-derived prodrugs of sobetirome with increased blood-brain barrier penetration. Bioorg Med Chem 25:2743-2753
Meinig, J Matthew; Ferrara, Skylar J; Banerji, Tania et al. (2017) Targeting Fatty-Acid Amide Hydrolase with Prodrugs for CNS-Selective Therapy. ACS Chem Neurosci 8:2468-2476
Ma, Hongwei; Yang, Fan; Butler, Michael R et al. (2017) Inhibition of thyroid hormone receptor locally in the retina is a therapeutic strategy for retinal degeneration. FASEB J 31:3425-3438
Placzek, Andrew T; Ferrara, Skylar J; Hartley, Meredith D et al. (2016) Sobetirome prodrug esters with enhanced blood-brain barrier permeability. Bioorg Med Chem 24:5842-5854

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