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...

In the present study we investigate whether augmentation of pharmacophores with excluded (ligand-inaccessible) volumes can condense the lengthy unspecific hit lists often obtained in 3D-database searching. Our pharmacophores contained hydrophobic features defined by the hormone, hydrogen bond donor and acceptor features of the liganded rat THR-alpha X-ray structure, and excluded volumes located at the positions and scaled according to the sizes of atoms delineating the binding cavity. We now show, for the first time, that it is perfectly feasible with the Catalyst software to search, in 1-2 h, medium-sized databases such as Maybridge (with 5 x 10(5) compounds registered as multiple conformers) with pharmacophores containing numerous (approximately 10(2)) excluded volumes. The excluded volumes did not slow the search significantly; for pharmacophores containing more features they also reduced the size of the hit list the most. For example, with a 7-feature pharmacophore, the Maybridge hit list shrank from 4 to 1. The single remaining compound was subsequently shown to bind to THR-alpha with an IC50 of 69 microM. Thus, we conclude that structure-based pharmacophores augmented with numerous excluded volumes can effectively prune and focus hit lists. The performance of multiple excluded volume-supplemented structure-based pharmacophores in 3D-database mining as implemented with the Catalyst software compares very favorably with other published procedures, with respect to speed, specificity, and ease of use.

Based on the recently described concept of "indirect antagonism" of nuclear receptors, a series of thyroid hormone receptor (TR) antagonists were prepared, in which the outer ring of a thyromimetic was replaced with alkyl chains of variable length and branch. The results of a binding assay for the human TR and reporter cell assay revealed, within this series, a positive correlation between increasing bulk of the alkyl group and affinity to TRs. Compared with already reported TR antagonists, their affinities are within the same range, thus potentially representing a useful approach to novel and high affinity TR-antagonists.