Thyroid hormone receptors are members of the nuclear hormone receptor family. Thyroid hormone (T3) is known to have a positive effect on levels of cholesterol and triglycerides, primarily through its action at the thyroid hormone receptor beta (THR-�) in the liver. Many of the adverse effects of hyperthyroidism, including cardiac effects, are mediated by thyroid hormone receptor alpha (THR-a). We report the discovery and SAR of a series of selective THR-� agonists. This series was optimized for THR-� selectivity and minimal THR-a activity, lack of activity in a micronucleus test, high liver exposure and absence of cardiotoxicity, leading to the identification of MGL-3196. Dosed orally, MGL-3196 exhibits beneficial effects on cholesterol and liver triglycerides while maintaining normal levels of thyroid hormones and TSH in preclinical models. MGL-3196 is currently in clinical development for the treatment of hypercholesterolemia/dyslipidemia and hypertriglyceridemia. The PK and lipid results from Phase I studies will be presented.

Discovery and development of MGL-3196, a liver-directed thyroid hormone beta agonist for the treatment of hypercholesterolemia/dyslipidemia and hypertriglyceridemia

245th National Meeting (2013)

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