Few treatments for obesity exist and, whereas efficacious therapeutics for hyperlipidemia are available, further improvements are desirable. Thyroid hormone receptors (TRs) regulate both body weight and cholesterol levels. However, thyroid hormones also have deleterious effects, particularly on the heart. The TR␤ subtype is involved in cholesterol lowering and possibly elevating metabolic rate, whereas TR␣ appears to be more important for control of heart rate (HR). In the current studies, we examined the effect of TR␤ activation on metabolic rate and HR with either TR␣1 ؊͞؊ mice or the selective TR␤ agonist KB-141 in mice, rats, and monkeys. 3,5,3 -triiodi-L-thyronine (T3) had a greater effect on increasing HR in WT than in TR␣ ؊͞؊ mice (ED15 values of 34 and 469 nmol͞kg͞day, respectively). T 3 increased metabolic rate [whole body oxygen consumption (MV O 2 )] in both WT and TR␣ ؊͞؊ mice, but the effect in the TR␣ 1 ؊͞؊ mice at the highest dose was half that of the WT mice. Thus, stimulation of MV O 2 is likely due to both TR␣ and -␤. T3 had equivalent potency for cholesterol reduction in WT and TR␣ ؊͞؊ mice. KB-141 increased MVO 2 with selectivities of 16.5-and 11.2-fold vs. HR in WT and TR␣ 1 ؊͞؊ mice, respectively. KB-141 also increased MV O 2 with a 10-fold selectivity and lowered cholesterol with a 27-fold selectivity vs. HR in rats. In primates, KB-141 caused significant cholesterol, lipoprotein (a), and body-weight reduction (up to 7% after 1 wk) with no effect on HR. TR␤-selective agonists may constitute a previously uncharacterized class of drugs to treat obesity, hypercholesterolemia, and elevated lipoprotein (a).O besity and atherosclerosis are important medical problems with major impact on morbidity and mortality. Current treatments for obesity have shown limited efficacy and safety; therefore, there is a need for improved therapies (1). A major risk factor for atherosclerosis is low-density lipoprotein (LDL) cholesterol. Although there are excellent treatments for elevated LDL cholesterol, therapeutic goals are commonly not met. As targets for lowering of cholesterol become more aggressive, there is a need for more modalities to meet these goals. Lipoprotein (a) [Lp(a)] is an important risk factor, elevated in many patients with premature atherosclerosis, and few therapies lower Lp(a) (2).Thyroid hormones reduce body weight, LDL cholesterol, and Lp(a); thus, exploitation of these properties may be useful for therapy (3-6). Unfortunately, endogenous thyroid hormones are nonselective and produce undesirable side effects, particularly cardiac stimulation (7,8). Development of thyromimetics devoid of cardiac effects could have therapeutic potential as antiobesity and lipid-lowering agents.Thyroid hormone receptors (TRs) are divided into two primary subtypes (TR␣ and -␤), which are the products of two genes of the superfamily of nuclear hormone receptors (4, 7). TRs mediate distinct physiologic effects due to differences in tissue abundance or receptor-specific activity (9). Studies in patients with th...

Endogenous thyroid receptor hormones 3,5,3',5'-tetraiodo-l-thyronine (T(4), 1) and 3,5,3'-triiodo-l-thyronine (T(3), 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 TRalpha(1) isoform, while most actions of the hormones on the liver and other tissues are mediated more through the TRbeta(1) 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 beta-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 TRbeta(1) over TRalpha(1). These ligands could potentially be useful for treatment of various disorders as outlined above. From a series of homologous R(1)-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 alpha(1) and beta(1) (TRalpha(1) and TRbeta(2)) as well as a reporter cell assay employing CHOK1-cells (Chinese hamster ovary cells) stably transfected with hTRalpha(1) or hTRbeta(1) and an alkaline phosphatase reporter-gene downstream thyroid response element (TRAFalpha(1) and TRAFbeta(1)). Affinity increases in the order formic, acetic, and propionic acid, while beta-selectivity is highest when the R(1) 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 reveal the most promising in vitro data based on isoform selectivity and were selected for further in vivo studies. The effect of 2, 11a, and 15 in a cholesterol-fed rat model was monitored including potencies for heart rate (ED(15)), cholesterol (ED(50)), and TSH (ED(50)). Potency for tachycardia was significantly reduced for the TRbeta selective compounds 11a and 15 compared with 2, while both 11a and 15 retained the cholesterol-lowering potency of 2. This left an approximately 10-fold ...