Thyroid Receptor Ligands. 1. Agonist Ligands Selective for the Thyroid Receptor β1

Endogenous thyroid receptor hormones 3,5,3‘,5‘-tetraiodo-l-thyronine (T4, 1) and 3,5,3‘-triiodo-l-thyronine (T3, 2) exert a significant effects on growth, development, and homeostasis in mammals. They regulate important genes in intestinal, skeletal, and cardiac muscles, the liver, and the central nervous system, influence overall metabolic rate, cholesterol and triglyceride levels, and heart rate, and affect mood and overall sense of well being. The literature suggests many or most effects of thyroid hormones on the heart, in particular on the heart rate and rhythm, are mediated through the TRα1 isoform, while most actions of the hormones on the liver and other tissues are mediated more through the TRβ1 isoform of the receptor. Some effects of thyroid hormones may be therapeutically useful in nonthyroid disorders if adverse effects can be minimized or eliminated. These potentially useful features include weight reduction for the treatment of obesity, cholesterol lowering for treating hyperlipidemia, amelioration of depression, and stimulation of bone formation in osteoporosis. Prior attempts to utilize thyroid hormones pharmacologically to treat these disorders have been limited by manifestations of hyperthyroidism and, in particular, cardiovascular toxicity. Consequently, development of thyroid hormone receptor agonists that are selective for the β-isoform could lead to safe therapies for these common disorders while avoiding cardiotoxicity. We describe here the synthesis and evaluation of a series of novel TR ligands, which are selective for TRβ1 over TRα1. These ligands could potentially be useful for treatment of various disorders as outlined above. From a series of homologous R1-substituted carboxylic acid derivatives, increasing chain length was found to have a profound effect on affinity and selectivity in a radioreceptor binding assay for the human thyroid hormone receptors α1 and β1 (TRα1 and TRβ2) as well as a reporter cell assay employing CHOK1-cells (Chinese hamster ovary cells) stably transfected with hTRα1 or hTRβ1 and an alkaline phosphatase reporter-gene downstream thyroid response element (TRAFα1 and TRAFβ1). Affinity increases in the order formic, acetic, and propionic acid, while β-selectivity is highest when the R1 position is substituted with acetic acid. Within this series 3,5-dibromo-4-[(4-hydroxy-3-isopropylphenoxy)phenyl]acetic acid (11a) and 3,5-dichloro-4-[(4-hydroxy-3-isopropylphenoxy)phenyl]acetic acid (15) were found to revea