Selective Thyromimetics Using Receptor and Tissue Selectivity Approaches: Prospects for Dyslipidemia

Joharapurkar, Amit; Dhote, Vipin; Jain, Mukul

doi:10.1021/jm2004706

Cited by 28 publications

(21 citation statements)

References 182 publications

(642 reference statements)

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“…25) TH directly and indirectly reduces circulating TG levels. [7][8][9][10] Hence TH enhances hepatic uptake of LDL and decreases VLDL synthesis in the liver by activating reverse cholesterol transport (RCT) pathway. [26][27][28] As was expected, SKL-13784 dose-dependently reduced plasma TG levels with the dose of 2.0 mg/kg daily restoring these levels to normal (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…6) Both academia and industry are making numerous efforts to separate TH beneficial effects such as cholesterol lowering and body weight loss from their other hormonal functions. 3,[7][8][9][10] Studies in TR-mutant mice suggest that TRβ is responsible for the cholesterol-lowering effect of TH. [11][12][13] In addition, TRβ is predominantly expressed in the liver, where it accounts for approximately 80% of T 3 -binding TRs.…”

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confidence: 99%

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<i>In Vivo</i> Evaluation of 1-Benzyl-4-aminoindole-Based Thyroid Hormone Receptor β Agonists: Importance of Liver Selectivity in Drug Discovery

Takahashi

Asano²,

Maeda

et al. 2014

Biological & Pharmaceutical Bulletin

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We recently reported that the novel thyroid hormone receptor β (TRβ) selective agonists SKL-12846 and SKL-13784 reduce blood cholesterol levels without affecting thyroid-stimulating hormone (TSH) in cholesterol-fed rats. Our aim in this study was to elucidate what sets apart these SKL-compounds as TRβ agonists with no effect on TSH. To this end, we determined SKL-compounds pharmacokinetics and tissue distribution in normal rats and compared them to those of GC-1, a liver-selective TRβ agonist with concomitant effect on TSH. The present study explains why SKL-12846 and SKL-13784 have beneficial effects on lowering lipids without affecting heart rate and TSH production at the therapeutic dose in cholesterol-fed rats. In addition, we found that SKL-13784 shows no sign of escape phenomenon in fructose-fed rats. These results demonstrate the advantages of extremely high liver specificity to TRβ agonists. However, SKL-13784 has been found significantly to reduce endogenous T 4 levels at doses lower than its lipid-lowering dose, which may raise concerns over this compound's ability to alter thyroid hormone metabolism in the liver. While the mechanism by which SKL-13784 reduces endogenous T 4 levels is still unclear, our results would help design better liver-selective TRβ modulators.Key words thyroid hormone receptor β; thyroid stimulating hormone; lipid-lowering effect; GC-1 Thyroid hormones (THs) are known to influence all major metabolic pathways including growth, development, and lipids metabolism. The involvement of THs in lipids metabolism was first reported in 1930, 1) and since then, accumulating evidence has shown that THs lower cholesterol levels in patients with hypercholesterolemia.2-4) TH synthesis and secretion are strictly regulated by the hypothalamic/pituitary/thyroid (HPT) axis, and their physiological action is modulated via two homologous TH receptors, TRα and TRβ, which belong to the nuclear receptor superfamily of ligand-dependent transcription factors.5) Because TH receptors are ubiquitously expressed in humans, plasma levels of circulating TH affect various physiological pathways and are associated with a number of pathological states such as hyperthyroidism, which is characterized by decreased serum cholesterol and triacylglycerides (TG) levels, body weight loss, tachycardia, palpitation, muscle wasting, and osteoporosis in postmenopausal women. 6)Both academia and industry are making numerous efforts to separate TH beneficial effects such as cholesterol lowering and body weight loss from their other hormonal functions.3,7-10) Studies in TR-mutant mice suggest that TRβ is responsible for the cholesterol-lowering effect of TH.11-13) In addition, TRβ is predominantly expressed in the liver, where it accounts for approximately 80% of T 3 -binding TRs. 14)Therefore a number of liver-selective TRβ agonists have been developed. Among them, GC-1 (Fig. 1) and KB2115 showed promising clinical trial results, but never reached the market probably due to undesirable side effects.10) Considering their drawb...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

<i>In Vivo</i> Evaluation of 1-Benzyl-4-aminoindole-Based Thyroid Hormone Receptor β Agonists: Importance of Liver Selectivity in Drug Discovery

Takahashi

Asano²,

Maeda

et al. 2014

Biological & Pharmaceutical Bulletin

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“…[137] X-ray structures of LBD from both receptor isoforms complexed with T3 have been reported in the literature.T he cocrystal structure of the LBD of human TRa1a nd T3 show that T3 is completely buried in ah ydrophobic pocket within the LBD (Figure 11 B). [138] This hormone-binding pocket is formed from several helices and loops of LBD,s uch as residues from helix 5-6 (H5-6, Met 256-Arg 266), helix 7-8 (H7-8), and the intervening loop (Leu 287-Ile 299), helix 3( H3, Phe 215-Arg 228), helix 11 (H11, His 381-His 387), and helix 12 (H12, Phe 401-Phe 405).…”

Section: Thyroid Hormone Receptorsmentioning

confidence: 99%

Chemistry and Biology in the Biosynthesis and Action of Thyroid Hormones

et al. 2016

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Thyroid hormones (THs) are secreted by the thyroid gland. They control lipid, carbohydrate, and protein metabolism, heart rate, neural development, as well as cardiovascular, renal, and brain functions. The thyroid gland mainly produces l-thyroxine (T4) as a prohormone, and 5'-deiodination of T4 by iodothyronine deiodinases generates the nuclear receptor binding hormone T3. In this Review, we discuss the basic aspects of the chemistry and biology as well as recent advances in the biosynthesis of THs in the thyroid gland, plasma transport, and internalization of THs in their target organs, in addition to the deiodination and various other enzyme-mediated metabolic pathways of THs. We also discuss thyroid hormone receptors and their mechanism of action to regulate gene expression, as well as various thyroid-related disorders and the available treatments.

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“…[20,148,149]), and some of these compounds may promote the development of an atherogenic lipid profile. Similarly, thyroid hormone is known to play a critical role in lipoprotein metabolism [150]. Disruption of thyroid hormone action has also been described for a number of different EDCs, including hydroxylated PCBs [151,152].…”

Section: Mechanisms Of Edc-induced Metabolic Dysregulation and Cardiomentioning

confidence: 99%

Environmental Endocrine Disruption of Energy Metabolism and Cardiovascular Risk

Kirkley

Sargis

2014

Curr Diab Rep

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Rates of metabolic and cardiovascular diseases have increased at an astounding rate in recent decades. While poor diet and physical inactivity are central drivers, these lifestyle changes alone fail to fully account for the magnitude and rapidity of the epidemic. Thus, attention has turned to identifying novel risk factors, including the contribution of environmental endocrine disrupting chemicals. Epidemiological and preclinical data support a role for various contaminants in the pathogenesis of diabetes. In addition to the vascular risk associated with dysglycemia, emerging evidence implicates multiple pollutants in the pathogenesis of atherosclerosis and cardiovascular disease. Reviewed herein are studies linking endocrine disruptors to these key diseases that drive significant individual and societal morbidity and mortality. Identifying chemicals associated with metabolic and cardiovascular disease as well as their mechanisms of action is critical for developing novel treatment strategies and public policy to mitigate the impact of these diseases on human health.

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Selective Thyromimetics Using Receptor and Tissue Selectivity Approaches: Prospects for Dyslipidemia

Cited by 28 publications

References 182 publications

<i>In Vivo</i> Evaluation of 1-Benzyl-4-aminoindole-Based Thyroid Hormone Receptor β Agonists: Importance of Liver Selectivity in Drug Discovery

<i>In Vivo</i> Evaluation of 1-Benzyl-4-aminoindole-Based Thyroid Hormone Receptor β Agonists: Importance of Liver Selectivity in Drug Discovery

Chemistry and Biology in the Biosynthesis and Action of Thyroid Hormones

Environmental Endocrine Disruption of Energy Metabolism and Cardiovascular Risk

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