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 mean time to peak concentration is 1.0 to 2.5 hours. Bioavailability has been reported as <1% but studies of repeat doses of inhaled corticosteroids suggest a bioavailability of 11%. The 0.1% ointment may have a bioavailability of 0.7%.
For an inhaled dose, approximately 74% is excreted in the feces and 8% is excreted in the urine.
Steady state volume of distribution of 152L.
The clearance rate of mometasone furoate is not readily available, though it may be close to 90L/h.

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Metabolism / Metabolites
Metabolism of mometasone furoate is largely performed hepatically by cytochrome P450 3A4 producing a number of metabolites. Some of these metabolites include free mometasone and 6-beta-hydroxy-mometasone furoate.

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Biological Half-Life
The terminal half life of an inhaled dose is approximately 5 hours though it has been reported as 5.8 hours by other sources.

Protein Binding
98% to 99% (in vitro concentration of 5 to 500ng/mL).

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441336 rat LD50 subcutaneous 300 mg/kg LUNGS, THORAX, OR RESPIRATION: RESPIRATORY DEPRESSION Kiso to Rinsho. Clinical Report., 24(4203), 1990
441336 mouse LDLo subcutaneous 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, a steroid ester, an 11beta-hydroxy steroid, a 20-oxo steroid, an organochlorine compound and a 3-oxo-Delta(1),Delta(4)-steroid. It has a role as an anti-inflammatory drug and an anti-allergic agent. It is functionally related to a mometasone.
Mometasone furoate is a corticosteroid drug that can be used for the treatment of asthma, rhinitis, and certain skin conditions. It has a glucocorticoid receptor binding affinity 22 times stronger than [dexamethasone] and higher than many other corticosteroids as well. Mometasone furoate is formulated as a dry powder inhaler, nasal spray, and ointment for its different indications.
Mometasone Furoate is the furoate ester form of mometasone, a synthetic topical glucocorticoid receptor (GR) agonist with anti-inflammatory, anti-pruritic and vasoconstrictive properties. Upon administration, mometasone binds to cytoplasmic GRs and subsequently activates GR-mediated gene expression. This results in the synthesis of certain anti-inflammatory proteins, while inhibiting the synthesis of certain inflammatory mediators. Specifically, mometasone appears to induce phospholipase A2 inhibitory proteins, thereby controlling the release of the inflammatory precursor arachidonic acid from phospholipid membrane by phospholipase A2.
A pregnadienediol derivative ANTI-ALLERGIC AGENT and ANTI-INFLAMMATORY AGENT that is used in the management of ASTHMA and ALLERGIC RHINITIS. It is also used as a topical treatment for skin disorders.
See also: Mometasone (has active moiety); Formoterol fumarate; mometasone furoate (component of); Florfenicol; Mometasone furoate; Terbinafine (component of) ... View More ...

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Drug Indication
Inhaled mometasone furoate is indicated for prophylaxis of asthma in patients ≥4 years. Applied topically as an ointment, mometasone furoate is indicated for symptomatic treatment of dermatitis and pruritis in patients ≥2 years. Mometasone furoate nasal spray is available both over-the-counter (OTC) and by prescription. The OTC nasal spray formulation of mometasone furoate is indicated for the treatment of upper respiratory allergic symptoms (e.g. rhinorrhea, sneezing) in patients ≥2 years of age. The prescription formulation is indicated for the treatment of chronic rhinosinusitis with nasal polyps in patients ≥18 year old and for the and prophylaxis of seasonal allergic rhinitis in patients ≥12 years old. It is also approved in combination with [olopatadine] for the symptomatic treatment of seasonal allergic rhinitis in patients ≥12 years.
FDA Label
Seasonal and perennial allergic rhinitis

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Mechanism of Action
In asthma, mometasone is believed to inhibit mast cells, eosinophils, basophils, and lymphocytes. There is also evidence of inhibition of histamine, leukotrienes, and cytokines. Corticosteroids diffuse across cell membranes into the cytosol of cells where they bind to glucocorticoid receptors to produce their activity. Mometasone furoate has a particularly high receptor affinity compare to other corticosteroids, 22 times higher than that of [dexamethasone]. Mometasone furoate binding to a glucocorticoid receptor causes conformational changes in the receptor, separation from chaperones, and the receptor moves to the nucleus. Once at the nucleus, receptors dimerize and bind to a DNA sequence known as the glucocorticoid response element which either increases expression of anti-inflammatory molecules or inhibits expression of pro-inflammatory molecules (such as interleukins 4 and 5). Mometasone furoate also reduces inflammation by blocking transcription factors such as activator-protein-1 and nuclear factor kappa B (NF-kappaB).

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Pharmacodynamics
Mometasone is a synthetic corticosteroid with an affinity for glucocorticoid receptors 22 times higher than that of [dexamethasone]. Mometasone furoate also has a lower affinity to mineralocorticoid receptors than natural corticosteroids, making it more selective in its action. Mometasone furoate diffuses across cell membranes to activate 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.)