Thyroid Hormones and Thyromimetics

Ryono, Denis E.; Grover, Gary J.; Mellström, Karin

doi:10.1002/0471266949.bmc052

Cited by 5 publications

(4 citation statements)

References 179 publications

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“…There is a large literature on SAR of thyromimetics that has been reviewed (39). The SAR is fairly constrained as it is difficult to make major modifications of the basic diphenyl ether scaffold.…”

Section: Discussion and Future Directionsmentioning

confidence: 99%

“…The most common form of hyperthyroidism is Graves' disease that is due to autoimmune antibodies that bind to and activate TSH receptors on the thyroid gland. The cardiac effects (positive chronotropy and inotropy) are due to the direct effects of TR stimulation of the heart, an excessive increase in metabolic rate as well as increased sensitivity of adrenoceptors (39).…”

Section: Endogenous Thyroid Hormonesmentioning

confidence: 99%

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Development of the Thyroid Hormone Receptor β-Subtype Agonist KB-141 : A Strategy for Body Weight Reduction and Lipid Lowering with Minimal Cardiac Side Effects

Grover

Mellström

Malm

2006

Cardiovascular Drug Reviews

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Few treatments for obesity exist and improvements for treatment of hyperlipidemia are still desirable. Thyroid hormone receptors (TRs) regulate body weight, adiposity, and cholesterol levels. However, thyroid hormones can have deleterious effects, particularly cardiac acceleration, that limits the use of hormones in the treatment of obesity. There is evidence that the TRâ subtype mediates lowering of blood cholesterol levels and possibly elevation of metabolic rate, whereas TRá appears to control heart rate. In studies, described in this review article, we examined the effects of selective TRâ activation on metabolic rate and heart rate in mice, rats and monkeys. T 3 had a greater effect on increasing heart rate in wild type (WT) than in TRá -/-mice (ED 15 values of 34 and 469 nmol/kg/day, respectively). T 3 increased metabolic rate (MVO 2 ) in both WT and TRá -/-mice, but the effect on TRá -/-mice was less pronounced compared to WT mice. Stimulation of MVO 2 is mediated by both TRá and TRâ, but with different profiles. In cholesterol-fed rats, KB-141, a selective TRâ agonist, increased MVO 2 with a 10-fold selectivity and lowered cholesterol with a 27-fold selectivity vs. tachycardia. In primates, KB-141 caused significant, cholesterol, Lp(a) and body weight reduction after 1 week of treatment with no effect on heart rate. These data suggest that selective TRâ agonists may represent a novel class of drugs for the treatment of obesity, hypercholesterolemia and elevated Lp(a), which may make them useful therapeutics for patients with metabolic syndrome.

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Section: Discussion and Future Directionsmentioning

confidence: 99%

Section: Endogenous Thyroid Hormonesmentioning

confidence: 99%

Development of the Thyroid Hormone Receptor β-Subtype Agonist KB-141 : A Strategy for Body Weight Reduction and Lipid Lowering with Minimal Cardiac Side Effects

Grover

Mellström

Malm

2006

Cardiovascular Drug Reviews

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“…The most common form of hyperthyroidism is Graves' disease that is due to autoimmune antibodies that bind to and activate TSH receptors on the thyroid gland. The cardiovascular effects (positive chronotropy and positive inotropy) are due to the direct effects of TR stimulation on the heart [13,30], are also secondary to excessive metabolic rate stimulation, in addition to increased sensitivity of adrenoceptors [13]. This is just a list of the most relevant changes for this review, but this is certainly not a complete list of symptoms and effects of these diseases.…”

Section: Pathophysiology Of the Thyroid Path-waymentioning

confidence: 99%

Therapeutic Potential for Thyroid Hormone Receptor-β Selective Agonists for Treating Obesity, Hyperlipidemia and Diabetes

Grover

Mellström²,

Malm³

2007

CVP

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Obesity and metabolic syndrome are increasing dramatically worldwide, contributing to cardiovascular morbidity and mortality. There are currently few safe and efficacious therapeutics for obesity and most strategies are focused on appetite suppression. Thyroid hormones reduce adiposity via increased metabolic rate, but unfortunately they cause large changes in metabolic rate and direct cardiac acceleration, making them useless for treating obesity. Thyroid hormone receptors (TRs) work as transcription factors and two subtypes exist: TRalpha and TRbeta. TRalpha mediates tachycardia and much of the metabolic rate effect, while TRbeta mediates cholesterol and TSH lowering effects of thyroid hormones. TRbeta activation modestly increases metabolic rate such that a therapeutic window of 5-10 fold increases in metabolic rate can be seen without tachycardia. This was initially studied in TRalpha(1)(-/-) mice. Recent structure activity work has resulted in the discovery of several TRbeta selective thyromimetics such as KB-141. Studies with KB-141 show that it has a 10-fold window in which therapeutic increases in metabolic rate are seen without tachycardia or cardiac hypertrophy. This agent lowers cholesterol in rats and primates. In primates, KB-141 causes significant weight and cholesterol reduction in addition to the independent risk factor Lp(a). These effects were seen without any effect on heart rate, unlike thyroid hormone (T(3)). Further work with TRbeta selective agents is warranted and recent work suggests the possibility of developing compounds that selectively penetrate different tissues which may have an even more desirable therapeutic window. Selective thyromimetics, therefore, may be useful as adjunctive therapy to appetite suppressants along with exercise and diet restriction.

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“…Several book chapters up to 1990 are available that describe these assays and summarize this large body of SAR [208,210,211]. The SAR of this class of compounds has also been summarized in the 6th edition of Burger's Medicinal Chemistry and Drug Discovery [212]. The general conclusions drawn from this early work could later relatively be well validated by the conclusions drawn from subsequent X-ray studies of ligand binding.…”

Section: Summary Of Early Structure-activitymentioning

confidence: 99%