Endocrine Abstracts

Thyroid hormones T₄ and T₃ regulate many different physiological processes in different tissues in vertebrates. Most of the actions of thyroid hormones are mediated by the thyroid hormone receptor (TR), which is a member of the nuclear receptor superfamily of ligand-activated transcription regulators. There are two different genes that encode two different TRs, TR alpha and TR beta, and these two TRs are often co-expressed at different levels in different tissues. TRα is the major TR in the heart, and is crucial for heart rate and for cardiac contractility and relaxation, whereas TRβ is the predominant TR isoform in the liver and is important for lipid metabolism. Compounds that selectively modulate thyroid hormone action by functioning as isoform-selective agonists or antagonists of the TRs might be useful for medical therapy. We present here the design, synthesis and biopharmacological profile of a series of halogen free TH analogs, either agonists or antagonists, structurally related to our TRbeta selective lead compound GC-1, also known as QRX-431 and Sobetirome, which recently completed Phase I clinical studies as a cholesterol-lowering agent. Selective thyroid hormone modulators provide useful experimental probes to better define thyroid hormone actions, and most importantly some of them have the potential to become novel therapeutic agents.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.