Clinical prospects for new thyroid hormone analogues

Purpose of review: Scientists have been studying liver-selective thyroid hormone analogues developed between the late 1980s through the late 1990s to validate their utility in treating hypercholesterolemia, diabetes, atherosclerosis, and obesity. Several thyromimetics with agonistic or antagonist properties have recently been developed and their clinical utility is being explored. This review presents the progress of several thyromimetics with potential clinical utility and provides an assessment of the potential of second-generation thyromimetics with varying pharmacologic profiles. Recent findings: GC-1 exhibits cholesterol-lowering effects in hypothyroid mice, cholesterol-fed rats, and cynomolgus monkeys. DITPA (3,5-diiodothyropropionic acid) is currently being investigated for use in treating congestive heart failure. In rat and rabbit postinfarction models, DITPA administration in combination with captopril or as monotherapy caused an increase in cardiac output and a decrease in left ventricular end-diastolic pressure without chronotropic or significant metabolic effects. DITPA treatment induces arteriolar growth and improves maximal perfusion potential of hypertrophied myocardium surviving a myocardial infarction. Thyroid hormone receptor-β-selective agonists, GC-24, KB-141, and KAT-681, as well as the thyroid hormone receptor-α-selective and thyroid hormone receptor-β-selective antagonists dronedarone and NH-3 show promise in treating hypercholesterolemia, hyperlipidemia, hepatocarcinogenesis, heart failure, and hyperthyroidism. Summary: Thyroid hormone receptors orchestrate a diverse array of physiologic activities in an isoform-specific manner. These activities include fetal and postnatal development, regulation of lipid inventory, and effects on cardiac performance. As a result, thyroid hormone analogues that selectively modulate thyroid hormone receptor isoforms serve as potential therapeutics in treating several metabolic and cardiac-related diseases.