Selective thyroid hormone receptor modulators

Abstract

Thyroid hormone (TH) is known to have many beneficial effects on vital organs, but its extrapolation to be used therapeutically has been restricted by the fact that it does have concurrent adverse effects. Recent finding of various thyroid hormone receptors (TR) isoforms and their differential pattern of tissue distribution has regained interest in possible use of TH analogues in therapeutics. These findings were followed by search of compounds with isoform-specific or tissue-specific action on TR. Studying the structure–activity relationship of TR led to the development of compounds like GC1 and KB141, which preferentially act on the β1 isoform of TR. More recently, eprotirome was developed and has been studied in humans. It has shown to be effective in dyslipidemia by the lipid-lowering action of TH in the liver and also in obesity. Another compound, 3,5-diiodothyropropionic acid (DITPA), binds to both α- and β-type TRs with relatively low affinity and has been shown to be effective in heart failure (HF). In postinfarction models of HF and in a pilot clinical study, DITPA increased cardiac performance without affecting the heart rate. TR antagonists like NH3 can be used in thyrotoxicosis and cardiac arrhythmias. However, further larger clinical trials on some of these promising compounds and development of newer compounds with increased selectivity is required to achieve higher precision of action and avoid adverse effects seen with TH.

A Renewed Focus on the Association Between Thyroid Hormones and Lipid Metabolism

“…TH has been shown to be effective in dyslipidemia, via its lipid-lowering action in the liver, and also in obesity. This differential pattern of TRs distribution stimulated the search for compounds with tissue-specific action on TR, leading to the development of compounds like GC1 and KB141 which selectively act on the β1 isoform of TR ( 86 ). The selective TRβ modulator GC-1 enhances several steps in reverse cholesterol transport and reduces serum cholesterol independently of LDL-R.…”

Both 3,5-Diiodo-L-Thyronine and 3,5,3′-Triiodo-L-Thyronine Prevent Short-term Hepatic Lipid Accumulation via Distinct Mechanisms in Rats Being Fed a High-Fat Diet

“…However, T3 may cause a clinical thyrotoxic state, characterized primarily by heart failure and skeletal muscle wasting. Recently, research has focused on identifying and developing thyroid hormone (TH) analogs that are both tissue- and TRβ- (the isoform predominantly involved in TH-induced hepatic metabolism) (Moreno et al, 2008 ) selective in order to stimulate hepatic metabolism without causing side effects particularly on the heart (Raparti et al, 2013 ).…”

Thyroid Hormone Receptors Predict Prognosis in BRCA1 Associated Breast Cancer in Opposing Ways

“…In addition, TRs have been reported to regulate a plethora of genes including those being involved in mediating cell differentiation, proliferation and apoptosis [ 7 , 8 ] and were found to be predictive for patient prognosis in hepatocellular carcinoma [ 8 ]. Since patients’ TR statuses can be determined easily by immunohistochemistry and as TRs were demonstrated to be accessible targets [ 6 , 9 ], TRs might be novel alternative biomarkers, especially for hormone receptor negative or even triple negative breast cancer patients. With a high percentage of BRCA1 associated breast cancers being classified as triple-negative, the assessment of TR expression in those patients may turn out to be attractive in terms of alternative treatment options, applicable especially for breast cancer patients carrying a BRCA1 germline mutation.…”