TR/thyroid hormone receptor

The Thyroid Hormone Analogue KB2115 (Eprotirome) Prolongs Human Hair Growth (Anagen) Ex Vivo.[3]
KB2115 did not significantly alter MTCO1 immunoreactivity, suggesting that the tested picomolar concentrations may not exert major effects on energy metabolism.[3]
KB2115 induced significantly smaller (if any) up-regulation of these genes in human HFs compared with T4. This supports the concept that KB2115 is less likely to exert unwanted systemic, mitochondrial activity-related adverse effects than T4.[3]
KB2115 treatment significantly increased the percentage of anagen HFs compared with vehicle controls (Figure 1a). Given that KB2115 thus effectively countered the tendency of organ-cultured HFs to spontaneously enter into catagen (Kloepper et al., 2010, Langan et al., 2015), our findings support the concept that KB2115 may prevent or reduce premature catagen entry leading to telogen effluvium in vivo.[3]
KB2115 also slightly but nonsignificantly increased hair bulb melanin content compared with vehicle control HFs, as assessed by quantitative Masson-Fontana histochemistry (Figure 2a–b). Moreover, KB2115 significantly increased the intrafollicular activity of tyrosinase in situ (Han et al., 2002) (Figure 2c–d), the rate-limiting enzyme of melanogenesis (Slominski et al., 2005). None of the tested KB2115 concentrations significantly altered the histochemically detected hair bulb melanin content or tyrosinase activity in situ compared with controls when exclusively anagen VI HFs were compared with each other (data not shown); therefore, this pigmentary effect of KB2115 most likely reflects prolonged anagen-associated intrafollicular melanogenesis (Han et al., 2002, Kloepper et al., 2010). However, further scrutiny is needed to determine whether long-term administration of KB2115 may also stimulate HF pigmentation in a hair cycle-independent manner and thus may also exert “anti-graying” actions.[3]
KB2115 significantly decreased transforming growth factor-β2 protein expression in the outer root sheath (Figure 2e–f). Surprisingly, intrafollicular IGF-1 protein expression was slightly decreased (see Supplementary Figure 4a–b online), suggesting that KB2115 may prolong anagen in an IGF-1–independent manner.[3]

Eprotirome is a thyroid hormone receptor agonist that selectively targets the liver. Lipid-filled vacuoles in the livers of untreated control mice were nearly entirely removed by iprotirol, according to histological examination of the livers of mice given the drug. Iptirol-treated mice likewise had higher fasting blood glucose levels, but not fasting insulin levels. The ipotirol-treated mice's blood glucose levels increased with time, resulting in marked hyperglycemia at the end of the trial. Compared to untreated control mice, animals treated with Eprotirom exhibited a drop in body temperature [1].

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Thyroid hormone receptor (TR) agonists have been proposed as therapeutic agents to treat non-alcoholic fatty liver disease (NAFLD) and insulin resistance. We investigated the ability of the TR agonists GC-1 and KB2115 to reduce hepatic steatosis in ob/ob mice. Both compounds markedly reduced hepatic triglyceride levels and ameliorated hepatic steatosis. However, the amelioration of fatty liver was not sufficient to improve insulin sensitivity in these mice and reductions in hepatic triglycerides did not correlate with improvements in insulin sensitivity or glycemic control. Instead, the effects of TR activation on glycemia varied widely and were found to depend upon the time of treatment as well as the compound and dosage used. Lower doses of GC-1 were found to further impair glycemic control, while a higher dose of the same compound resulted in substantially improved glucose tolerance and insulin sensitivity, despite all doses being equally effective at reducing hepatic triglyceride levels. Improvements in glycemic control and insulin sensitivity were observed only in treatments that also increased body temperature, suggesting that the induction of thermogenesis may play a role in mediating these beneficial effects. These data illustrate that the relationship between TR activation and insulin sensitivity is complex and suggests that although TR agonists may have value in treating NAFLD, their effect on insulin sensitivity must also be considered [3].

Several metabolic products that derive from L-thyroxine (T4) and 3,3'5-L-triiodothyronine (T3), the main thyroid hormones secreted by the thyroid gland, possess biologic activities. Among these metabolites or derivatives showing physiological actions some have received greater attention: diiodothyronines, iodothyronamines, acetic acid analogues. It is known that increased thyroid hormone (T3 and T4) levels can improve serum lipid profiles and reduce body fat. These positive effects are, however, counterbalanced by adverse effects on the heart, muscle and bone, limiting their use. In addition to the naturally occurring metabolites, thyroid hormone analogues have been developed that either have selective effects on specific tissues or bind selectively to thyroid hormone receptor (TR) isoform. Among these GC-1, KB141, KB2115, and DITPA were deeply investigated and displayed promising therapeutic results in the potential treatment of conditions such as dyslipidemias and obesity. In this review, we summarize the current knowledge of metabolites and analogues of T4 and T3 with reference to their possible clinical application in the treatment of human diseases[1].

That the synthetic TR-modulator KB2115, which is expected to show reduced adverse effects compared with T4, promotes human HF growth ex vivo corroborates the recognized anagen-prolonging effect of endogenous THs (Billoni et al., 2000, van Beek et al., 2008). The apparently much lower impact of KB2115 than of T4 on mitochondrial activity parameters in human HF keratinocytes in situ suggests a favorable profile of systemic adverse effects, which may be further reduced by using a HF-targeting topical application vehicle (Vogt and Blume-Peytavi, 2014, Vogt et al., 2015). Also unlike T4 (van Beek et al., 2008), KB2115 did not increase HF pigmentation under the current assay conditions.[3]
Our ex vivo pilot data suggest that KB2115 is a promising candidate for the future treatment of hair loss disorders characterized by premature catagen entry, such as various forms of telogen effluvium and androgenetic alopecia (Paus, 2006, Qi and Garza, 2014), ideally after topical application. Thus, KB2115 may serve as a lead compound for the development of other hair growth-promoting agents with reduced toxicity compared with T4. However, given that systemic KB2115 treatment may lead to cartilage damage in dogs (Sjouke et al., 2014), further rigorous toxicological and pharmacokinetic screening is required before KB2115 is applied topically to the human scalp[3]

Hyperinsulinemic-euglycemic clamp[3]
A catheter was implanted into the right internal jugular vein before the hyperinsulinemic-euglycemic clamp. After recovery, mice were administered GC-1 (0.03 or 0.3 mg/kg), KB2115 (0.3 mg/kg) or T3 (0.06 mg/kg) via intraperitoneal injection for 10 days. On the day of the clamp experiment, conscious, overnight-fasted mice received a primed (10 μCi) and constant rate intravenous infusion (0.1 uCi/min) of [3-3H] glucose to measure basal glucose turnover. After 60–75 minutes of labeled glucose infusion, the hyperinsulinemic-euglycemic clamp was performed with continuous infusion of insulin (12 mU/kg/min) and variable infusion of 25% glucose to maintain euglycemia (~120 mg/dl). Blood samples were collected by tail bleeding (approximately every 10 min) to measure blood glucose concentrations.

[1]. Martagón AJ, et al. The amelioration of hepatic steatosis by thyroid hormone receptor agonists is insufficient to restore insulin sensitivity in ob/ob mice. PLoS One. 2015 Apr 7;10(4):e0122987.
[2]. Rosalba Senese, et al. Thyroid hormone metabolites and analogues. Endocrine. 2019 Oct;66(1):105-114.
[3]. The Thyroid Hormone Analogue KB2115 (Eprotirome) Prolongs Human Hair Growth (Anagen) Ex Vivo. J Invest Dermatol . 2016 Aug;136(8):1711-1714.

Eprotirome which is a compound with promising properties for treatment of obesity and dyslipidemia. Eprotirome increases the body’s energy consumption and reduces body weight and markedly reduces blood lipids and blood glucose.
Eprotirome is a thyroid hormone analog with hypocholesterolemic properties. Eprotirome reduces serum LDL cholesterol levels by increasing hepatic clearance due to increased expression of the hepatic LDL-receptor gene, and also reduces the serum level of Lp(a) lipoprotein. This drug was designed to have minimal uptake in nonhepatic tissues thereby avoiding many of the adverse effects associated with thyroid hormone treatment.

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Drug Indication
Investigated for use/treatment in hyperlipidemia, metabolic disease, and obesity.
Primary hypercholesterolaemia

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Mechanism of Action
KB2115 works by selectively stimulating the thyroid hormone receptor which is the protein in the body that mediates the effects of thyroid hormone. KB2115 has receptor and tissue selective properties and thereby negative effects on the heart can be avoided.

484.947

C, 44.38; H, 3.52; Br, 32.81; N, 2.88; O, 16.42

355129-15-6

355129-15-6;

10299876

White to light yellow solid powder

1.7±0.1 g/cm3

596.3±50.0 °C at 760 mmHg

314.4±30.1 °C

0.0±1.8 mmHg at 25°C

1.655

5.62

3

5

6

26

492

0

VPCSYAVXDAUHLT-UHFFFAOYSA-N

InChI=1S/C18H17Br2NO5/c1-9(2)12-7-11(3-4-15(12)22)26-18-13(19)5-10(6-14(18)20)21-16(23)8-17(24)25/h3-7,9,22H,8H2,1-2H3,(H,21,23)(H,24,25)

3-((3,5-Dibromo-4-(4-hydroxy-3-(1-methylethyl)phenoxy)phenyl)amino)-3-oxopropanoic acid

KB-2115; KB 2115; KB2115; KB-2115; KB2115; Eprotirome [INN]; CHEMBL2035874; Bms-356384; 958AQ7B6R1; Eprotirome.

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~125 mg/mL (~256.60 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (4.27 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (4.27 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (4.27 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)