Glucocorticoid Receptor/GR

Mometasone furoate attaches to a glucocorticoid receptor induces conformational changes in the receptor, separation from chaperones, and the receptor travels to the nucleus[1]. Mometasone furoate (0.1-10 μM; 2h before LPS stimulation) substantially suppresses LPS-stimulated nitrite generation in a concentration-dependent manner in J774 macrophages, The IC50 value is 0.00024 μM for Mometasone furoate in J774 cells[1]. Mometasone furoate (0.1-10 μM; 2h before LPS stimulation) is more powerful than DEX, it significantly reduces iNOS expression at a 0.01 µM dose whereas Dex became active at 0.1 µM. Additionally, the inhibition of cox-2 protein expression at 0.01 µM is 79% for Mometasone furoate and 39% for Dex[1].

Mometasone causes a decrease in the instances of nasal rubbing and an inhibition of this response is observed during the treatment period in rats. Mometasone (3 mg/kg) inhibits the increased airway sensitivity to aerosolized methacholine at the highest dose tested in mice. Mometasone, given an hour after the last allergen challenge, dose-dependently inhibits the allergen-induced increase in Penh with about a 10-fold loss of potency when compared with the pre-challenge treatment schedule. Mometasone furoate (0.02%) and fluticasone propionate (0.1%) significantly inhibits the increase of antigen-induced nasal rubbing even 6 hours after topical application, indicating that both drugs have a long-lasting effect. Mometasone furoate dose-dependently inhibits the elevated eosinophil numbers in the bronchoalveolar lavage fluid and lung tissues of sensitized, ovalbumin challenged mice. Mometasone furoate (33 mg/kg) reduces the percentage of CD44+ T-helper cells (activated/memory cells) to the levels observed in non-sensitized, ovalbumin-challenged mice.

Extracellular signal regulated kinase 1/2 (pERK1/2), PARP-1 and Bax expression [1]
Protein content for specific antibodies was evaluated in the spinal cord by SDS page electrophoresis and blotting according to standardized protocol for spinal cord tissues. Membranes were probed at 4 °C overnight with rabbit phospho-p44/42 MAPK (pERK1/2), rabbit PARP-1, rabbit Bax. Signal was developed following incubation with horseradish peroxidase-conjugated anti-rabbit for 1 h at room temperature and using an enhanced chemiluminescence system . p44/42 MAPK (ERK1/2) was used to normalize the signals of phospho-p44/42 MAPK, while β-actin and GAPDH were used to normalized PARP-1 and Bax expression, respectively.

The murine monocyte/macrophage J774 cell line was grown in Dulbecco’s modified Eagles medium (DMEM) supplemented with 2 mM glutamine, 25 mM Hepes, penicillin (100 U/ml), streptomycin (100 μg/ml), 10% foetal bovine serum (FBS) and 1.2% Na pyruvate. Cells were plated in 24-well culture plates at a density of 2.5 ± 105 cells/ml or in 60 mm-diameter culture dishes (3 ± 106 cells per 3 ml dish) and allowed to adhere at 37 °C in 5% CO2. After 24 h, cells were pre-treated (for 2 h) with increasing concentration of old (Dex and MET) and new mometasone furoate (MF) , and stimulated with LPS from Escherichia coli, Serotype 0111:B4, (10 μg/ml). After 24 h of treatment, the supernatants were collected for nitrite measurement[1].

Mice were randomly allocated into the following groups (n = 60 total animals): [1]
Sham group (n = 5): Mice not subjected to SCI but only to T5–T8 vertebrae exposition, sacrificed as control.[1]
SCI group (n = 10): Mice were subjected to surgical operations to induce SCI and injected with saline;[1]
SCI + mometasone furoate (MF)  (n = 10): Mice were subjected to surgical operations to induce SCI and treated with mometasone furoate (MF)  0.1 mg/Kg;[1]
SCI + Dex (n = 10): Mice were subjected to surgical operations to induce SCI and treated with Dex 1 mg/Kg;[1]
SCI + MPSS (n = 10): Mice were subjected to surgical operations to induce SCI and treated with MPSS 6 mg/Kg.[1]
In another experimental set, investigated drugs were preliminary tested in order to evaluate a more efficient dosage. Moreover, control groups (not included in the present work) designed as “Sham + mometasone furoate (MF)  ” (n = 5), “Sham + Dex” (n = 5), “Sham + MPSS” (n = 5), “Sham + vehicle (5% DMSO)” (n = 5) were tested to evaluate toxicity of GC as well as vehicle (DMSO) injection.[1]
Mice were treated i.p. 30 min following trauma induction and once a day for 7 days until sacrifice.[1]
Spinal cord area, corresponding to the thoracic spine, was sampled, in order to evaluate the various parameters.[1]

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3 mg/kg

ovalbumin-challenged mice

Absorption, Distribution and Excretion
The average time to peak concentration is 1.0 to 2.5 hours. Bioavailability has been reported to be less than 1%, but studies with repeated administration of inhaled corticosteroids have shown a bioavailability of 11%. The bioavailability of the 0.1% ointment may be 0.7%. Approximately 74% of the inhaled dose is excreted in feces, and 8% in urine. The steady-state volume of distribution is 152 liters. The clearance of mometasone furoate is not well understood, but is likely close to 90 liters/hour. Metabolism/Metabolites Mometasone furoate is primarily metabolized in the liver via cytochrome P450 3A4, producing several metabolites. These metabolites include free mometasone and 6-β-hydroxymometasone furoate. Biological Half-Life The terminal half-life of the inhaled dose is approximately 5 hours, but other sources have reported 5.8 hours.

Protein Binding
98% to 99% (in vitro concentrations of 5 to 500 ng/mL). 441336 Rats: Subcutaneous LD50 300 mg/kg. Lung, pleural cavity, or respiration: Respiratory depression. Kiso to Rinsho Clinical Report, 24(4203), 1990. 441336 Mice: Subcutaneous LDLo 1 gm/kg. Kiso to Rinsho Clinical Report, 24(4203), 1990.

[1]. Use of Mometasone furoate in prolonged treatment of experimental spinal cord injury in mice: A comparative study of three different glucocorticoids. Pharmacol Res. 2015 Sep;99:316-28.

[2]. https://go.drugbank.com/drugs/DB14512.

Mometasone furoate is a 2-furoate ester belonging to the steroidal ester, 11β-hydroxysteroid, 20-oxosteroid, organochlorine compound, and 3-oxo-Δ⁹Δ⁴steroid classes. It possesses anti-inflammatory and anti-allergic effects, functions of which are related to mometasone. Mometasone furoate is a corticosteroid used to treat asthma, rhinitis, and certain skin conditions. Its binding affinity to glucocorticoid receptors is 22 times that of dexamethasone and higher than many other corticosteroids. Mometasone furoate is available in dry powder inhalers, nasal sprays, and ointments for various indications. Mometasone furoate is the furoate ester form of mometasone, a synthetic topical glucocorticoid receptor (GR) agonist with anti-inflammatory, antipruritic, and vasoconstrictive effects. After administration, mometasone binds to cytoplasmic GR, subsequently activating GR-mediated gene expression. This leads to the synthesis of certain anti-inflammatory proteins while inhibiting the synthesis of certain inflammatory mediators. Specifically, mometasone appears to induce the expression of phospholipase A2 inhibitory protein, thereby controlling the release of the inflammatory precursor arachidonic acid from the phospholipase membrane by phospholipase A2. A pregnadiene glycol derivative with anti-allergic and anti-inflammatory effects, it is used to treat asthma and allergic rhinitis. It can also be used as a topical treatment for skin conditions. See also: mometasone (containing active ingredient); formoterol fumarate; mometasone furoate (ingredient); florfenicol; mometasone furoate; terbinafine (ingredient)... See more...

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Drug Indications
Inhaled mometasone furoate is indicated for asthma prevention in patients aged 4 years and older. Topical mometasone furoate ointment is indicated for the treatment of dermatitis and pruritus in patients aged 2 years and older. Mometasone furoate nasal spray is available in both over-the-counter (OTC) and prescription formulations. Over-the-counter mometasone furoate nasal spray is indicated for the treatment of upper respiratory tract allergy symptoms (such as runny nose and sneezing) in patients aged 2 years and older. This prescription drug is indicated for the treatment of chronic sinusitis with nasal polyps in patients aged 18 years and older, and for the treatment and prevention of seasonal allergic rhinitis in patients aged 12 years and older. It is also approved for use in combination with olopatadine for the treatment of symptoms of seasonal allergic rhinitis in patients aged 12 years and older.
FDA Label
Seasonal and Perennial Allergic Rhinitis

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Mechanism of Action
In asthma, mometasone furoate is thought to inhibit mast cells, eosinophils, basophils, and lymphocytes. There is also evidence that it inhibits histamine, leukotrienes, and cytokines. Corticosteroids diffuse across the cell membrane into the cytoplasm, where they bind to glucocorticoid receptors to exert their activity. Compared to other corticosteroids, mometasone furoate has a particularly high receptor affinity, 22 times higher than dexamethasone. The binding of mometasone furoate to glucocorticoid receptors causes a conformational change in the receptor, dissociating it from its molecular chaperone and translocating it into the cell nucleus. Once the receptor reaches the cell nucleus, it dimers and binds to DNA sequences called glucocorticoid response elements, thereby increasing the expression of anti-inflammatory molecules or inhibiting the expression of pro-inflammatory molecules (such as interleukins 4 and 5). Mometasone furoate can also reduce inflammation by blocking transcription factors such as activator protein-1 and nuclear factor-κB (NF-κB).

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Pharmacodynamics
Mometasone is a synthetic corticosteroid with an affinity for glucocorticoid receptors that is 22 times greater than that of dexamethasone. Mometasone furoate also has a lower affinity for mineralocorticoid receptors than natural corticosteroids, making its action more selective. Mometasone furoate can diffuse across the cell membrane and activate signaling pathways responsible for reducing inflammation.

C27H30CL2O6

521.43

520.14

C, 62.19; H, 5.80; Cl, 13.60; O, 18.41

83919-23-7

Mometasone furoate-d3; 141646-00-6 (furoate hydrate) 105102-22-5 (Mometasone)

441336

White to off-white solid powder

1.4±0.1 g/cm3

655.5±55.0 °C at 760 mmHg

218-220°C

350.2±31.5 °C

0.0±2.1 mmHg at 25°C

1.604

4.27

1

6

5

35

1020

8

WOFMFGQZHJDGCX-ZULDAHANSA-N

InChI=1S/C27H30Cl2O6/c1-15-11-19-18-7-6-16-12-17(30)8-9-24(16,2)26(18,29)21(31)13-25(19,3)27(15,22(32)14-28)35-23(33)20-5-4-10-34-20/h4-5,8-10,12,15,18-19,21,31H,6-7,11,13-14H2,1-3H3/t15-,18+,19+,21+,24+,25+,26+,27+/m1/s1

(8S,9R,10S,11S,13S,14S,16R,17R)-9-chloro-17-(2-chloroacetyl)-11-hydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl furan-2-carboxylate

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)

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.79 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 25.0 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 2: ≥ 2.5 mg/mL (4.79 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 25.0 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.)