Thyroid Hormone Analogues: Ready for Prime Time

C ertain metabolic and organ-specific actions of thyroid hormone have long intrigued clinical investigators and pharmaceutical companies with regard to potential benefits of targeting thyromimetic effects to specific tissues in order to treat “nonthyroidal” diseases such as hypercholesterolemia, obesity, heart failure, impaired skeletal remodeling, thyroid cancer, impaired cognition, and affective disorders. Enthusiasm for this class of agents has been tempered, however, by awareness that there are two classes of potential adverse effects of thyroid hormone analogues. First, a thyromimetic compound without sufficiently specific targeting might cause undesirable thyrotoxic effects in other tissues. For example, a drug intended to lower serum low-density lipoprotein (LDL) cholesterol through augmented hepatic thyroid hormone actions could also increase heart rate and accelerate bone turnover. Several previously studied thyroid hormone analogues have failed to clear this hurdle, including triiodothyroacetic acid (tiratricol, triac), which was investigated as a thyrotropin (TSH)-suppressing agent (1), and diiodothyroproprionic acid (DITPA), which was studied as a novel treatment for heart failure (2). Both of these agents proved to increase resting heart rate and elevate circulating markers of bone turnover. A second general class of adverse effects potentially associated with thyroid hormone analogues is preferential suppression of the hypothalamic–pituitary–thyroid axis, which could predictably result in peripheral tissue hypothyroidism such as has been shown to occur with the retinoid X receptor agonist bexarotene (3).

The most clinically attractive and often-sought thyromimetic actions—lipid lowering and calorigenesis—are primarily exerted in the liver. Several mechanisms can be envisioned for augmenting these hepatic thyroid hormone actions. One obvious strategy is to identify compounds that selectively bind and activate the β1 isoform of the nuclear thyroid hormone receptor (TRβ), which is highly expressed in liver, as opposed to the α1 isoform, which is expressed in the cardiac conducting system where augmenting thyroid hormone action accelerates heart rate and provokes tachyarrhythmias. Two previously studied analogues, sobetirome (GC-1, ORX431) (4) and eprotirome (KB2115) (5), achieve hepatic tissue specificity in part through such TRβ-binding specificity.

Targeting thyroid hormone action could also be achieved through preferential hepatocyte delivery by a profile of plasma protein binding or target tissue peptide transporter handling that is distinct from native thyroid hormones. Eprotirome, for example, appears to have such preferential hepatic access by mechanisms that are incompletely defined. Another approach to selective liver delivery has been exploited by the phosphonic acid–linked prodrug MB07811, which selectively enters hepatocytes and is then cleaved intracellularly to generate the TRβ agonist MB07344 (6). All three of these compounds—sobetirome, eprotirome, and MB07344—have shown impressive lipid-lowering properties in animal models. Furthermore, short-term human trials have confirmed the efficacy of eprotirome in lowering total and LDL cholesterol, triglycerides, and lipoprotein(a)—both as a single agent (3) and when added to statin therapy (7). In 2011, this compound will be further assessed in a larger and longer phase 3 clinical trial to test its efficacy and safety in patients with familial heterozygous hypercholesterolemia whose dyslipidemia is often inadequately controlled with statin therapy alone (8).

Another exciting horizon in thyroid hormone analogue research has arisen from the recognition that thyroid hormones exert nongenomic actions through binding to a plasma membrane receptor associated with integrin αvβ3 (9). Resulting cellular membrane ion fluxes have been shown to stimulate angiogenesis in striated muscle and tumor cells and to have anti-apoptotic effects on some tumor cells. It has recently been shown that the thyroid hormone analogue tetraiodothyroacetic acid (tetrac) can inhibit these angiogenic and tumor cell proliferative actions of thyroxine and triiodothyronine (10). Clinicians may soon hear of human trials investigating the anti-angiogenic potential of tetrac in conditions as disparate as glioblastoma and acne rosacea.

There are other potential contributions that thyroid hormone analogues might make to clinical medicine. Antagonists of thyroid hormone action could obviously have value in acute management of patients with severe thyrotoxicosis (11). Thyroid hormone analogues may have niche applications in patients with rare genetic disorders affecting thyroid hormone–interacting molecules, as illustrated by promising studies suggesting a role for DITPA in treatment of children with mutated monocarboxylate 8 transporters (12) and by the reputed TSH-suppressive value of tiratricol in isolated pituitary resistance to thyroid hormone with TRβ mutation (13).

In conclusion, advances in thyroid hormone analogue research over the past decade have brought this class of agents to the brink of clinical application for prevention and treatment of an array of conditions ranging from the most common and serious afflicting mankind (i.e., atherosclerosis, ischemia, and cancer) to some of the rarest. However, the ubiquitous actions of thyroid hormone demand that our enthusiasm for their use be tempered by vigilance for their potential adverse effects—“rounding up the usual suspects” so familiar to clinical thyroidologists whenever a patient with thyrotoxicosis or hypothyroidism appears before them.