Thyroid hormone antagonists: Potential medical applications and structure activity relationships

Johan Malm, Mathias Färnegårdh, Gary J. Grover, Paul W Ladenson

Research output: Contribution to journalArticle

Abstract

Thyroid hormone receptors (TRs) exert profound effects on development, metabolism, and multiple specific organ functions. Principally by regulating crucial genes in a variety of tissues, the thyroid hormones, 3,5,3′-triiodo-L-thyronine (L-T3, 1) and 3,5,3′,5′- tetraiodo-L-thyronine (L-T4, 2), influence basal calorigenesis and oxygen consumption, cardiac rate and contractility, lipid metabolism, bone structure and strength, and central nervous system functions critical for normal mentation and mood. Elevated levels of circulating and tissue 1 and/or 2 result in the thyrotoxic clinical state, manifested by weight loss despite increased caloric intake; heat intolerance due to increased calorigenesis; cardiac tachyarrhythmias, systolic hypertension, and heart failure; skeletal muscle weakness; and a spectrum of neuropsychiatric symptoms ranging from anxiety to delirium and psychosis. The current standard treatments of endogenous hyperthyroidism causing thyrotoxicosis reduce the overproduction of thyroid hormones by pharmacologically inhibiting their synthesis or release (e.g., with thionamides or lithium, respectively), or by ablating thyroid tissue surgically or with radioiodine. TR-antagonists could hypothetically have significant clinical use in treating thyrotoxic states if they were capable of promptly and completely restoring euthyroid levels of thyroid-specific gene activity. No TRα-selective ligands have been prepared up to this date, ligands that potentially would further ameliorate the problem with cardiac disease connected with hyperthyroidism and maybe cardiac arrhythmia. Despite its significant potential use, no TR-antagonist has reached clinical application. Design of TR-antagonists ligands has been based on the attachment of a large extension group at the 5-prime position of 1 or other structurally related analogues. This extension is believed to distort folding of the C-terminal helix (helix 12) to the body of the ligand binding domain (LBD), which normally forms a coactivator site. Examples of synthetic TR antagonists based on this extension strategy are reviewed, as well as other strategies to achieve functional TR-antagonism.

Original languageEnglish (US)
Pages (from-to)3258-3266
Number of pages9
JournalCurrent Medicinal Chemistry
Volume16
Issue number25
DOIs
StatePublished - 2009

Fingerprint

Hormone Antagonists
Antithyroid Agents
Thyroid Hormone Receptors
Medical applications
Structure-Activity Relationship
Thyroid Hormones
Thyronines
Ligands
Hyperthyroidism
Tissue
Thyroid Gland
Genes
Systolic Heart Failure
Thyrotoxicosis
Delirium
Muscle Weakness
Neurology
Energy Intake
Lipid Metabolism
Lithium

Keywords

  • Amiodarone
  • Design strategy
  • Hyperthyroidism
  • Structure-activity-relationship
  • Thyroid hormone antagonist
  • Thyroid hormone receptor
  • Thyrotoxicosis
  • X-ray structure

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Thyroid hormone antagonists : Potential medical applications and structure activity relationships. / Malm, Johan; Färnegårdh, Mathias; Grover, Gary J.; Ladenson, Paul W.

In: Current Medicinal Chemistry, Vol. 16, No. 25, 2009, p. 3258-3266.

Research output: Contribution to journalArticle

Malm, Johan ; Färnegårdh, Mathias ; Grover, Gary J. ; Ladenson, Paul W. / Thyroid hormone antagonists : Potential medical applications and structure activity relationships. In: Current Medicinal Chemistry. 2009 ; Vol. 16, No. 25. pp. 3258-3266.
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