Invited Speaker

Development of pharmaceuticals that exploit the thyroid hormone receptor
John D. Baxter, Paul Webb and Thomas Scanlan
USA

Thyroid hormone (TH) excess results in wanted effects such as promotion of fat loss and lowering of plasma LDL cholesterol levels, but also in unwanted effects on heart, bone and muscle. It would be medically useful to block, acutely, the unwanted effects in hyperthyroidism, given that current treatments for this disorder are slow acting. It would also be desirable to harness the beneficial effects without eliciting the deleterious effects. We are approaching both of these needs. Utilizing information about the structure of the TH receptor (TR) and other data, we are developing TR agonists and antagonists. This led to establishment of a number of principles for antagonist design which have resulted in new compounds that bind TRs with nanomolar affinity and are now being tested in animal models. TR agonists that are selective for receptor subtype, and liver and/or other tissue selective uptake (STRMs) are being developed by multiple groups, including our own. In animals, these compounds promote: lowering of plasma LDL cholesterol, triglycerides and lipoprotein(a); reverse cholesterol transport; loss of fat; and amelioration of diabetes, without eliciting obvious toxicity or effects on the heart in effective doses. In humans, the most extensively studied compound (KB2115) promotes major reductions in plasma LDL levels, even in patients treated with “statins”, triglycerides and lipoprotein(a), without eliciting harmful side effects over a 3 month period. These compounds therefore show promise for treating important diseases facing developed countries and, increasingly, other parts of the world.