Glucocorticoid receptor

Mapracorat has an IC50 value of about 0.2 nM and inhibits TNFα secretion from activated canine PBMC in a concentration-dependent manner.
Mapracorat concentration dependently inhibited TNFα secretion from activated canine PBMC with a half maximal inhibitory concentration (IC50) value of approximately 0.2 nmol/L.[1]

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Mapracorat significantly reduced IL-4 or IL-13 plus TNF-α-induced cytokine release and ICAM-1 protein in a dose-dependent manner in both cell types, with comparable efficacy to dexamethasone. These effects were mediated through the glucocorticoid receptor (GR), as demonstrated by the reversal of inhibitory effects after silencing of glucocorticoid receptor expression. Conclusions: Data from these in vitro models indicate that mapracorat is efficacious and potent in reducing IL-4 or IL-13 plus TNF-α-induced release of allergy-related and proinflammatory cytokines from the HConF and the HConEpiC, supporting clinical evaluation of the compound in reducing allergic and inflammatory reactions in allergic conjunctivitis. [2]

During the 60-minute observation period, compound 48/80 (50 μg in 50 μL of saline) administered intradermally caused notable wheal and flare reactions. When compared to areas treated with acetone, the topical pretreatment of Mapracorat (0.1%) dramatically decreased wheal and flare reactions.
Intradermal injection of compound 48/80 (50 μg in 50 μL saline) resulted in a clear wheal and flare reaction over the 60 min observation period. Topical pre-treatment with mapracorat (0.1%) and triamcinolone acetonide (0.015%) led to significant reduction in the wheal and flare responses compared to vehicle (acetone) treated areas. However, once daily topical administration of triamcinolone acetonide significantly reduced skin fold thickness from day 8 to 14, whereas no such reduction was observed for mapracorat. Conclusion These results demonstrate that mapracorat has comparable anti-inflammatory efficacy to classical steroidal glucocorticoids under these experimental settings and maintenance of skin fold thickness indicates a better safety profile compared to triamcinolone acetonide at equipotent concentrations. This profile further suggests that SEGRAs show promise in the management of inflammatory and pruritic skin diseases in dogs.[1]

Purpose: To determine the ocular anti-allergic effects of mapracorat, a novel selective glucocorticoid receptor agonist (SEGRA) in primary human conjunctival fibroblasts and epithelial cells.
Methods: Two primary human conjunctival cell types, human conjunctival epithelial cells (HConEpiC) and human conjunctival fibroblasts (HConF), were challenged with interleukin-4 (IL-4) or IL-13 plus tumor necrosis factor-alpha (TNF-α). Luminex technology was used to profile the resulting inflammatory response. The effects of mapracorat on the release of eotaxin and regulated on activation, normal T cell expressed and secreted (RANTES), two allergy-related chemokines, as well as proinflammatory cytokines and intercellular adhesion molecule 1 (ICAM-1) were then determined. Small interfering RNA was used to determine whether the effects of mapracorat were mediated via the glucocorticoid receptor (GR). Dexamethasone was used as the control.
Results: IL-13 or IL-4 plus TNF-α in the HConF or HConEpiC significantly increased eotaxin-1 (HConF only), eotaxin-3, RANTES, multiple proinflammatory cytokines, and ICAM-1. Synergistic effects of IL-13 or IL-4 plus TNF-α were observed in the HConEpiC for RANTES and monocyte chemoattractant protein-1, and in the HConF for eotaxin-1, eotaxin-3, and RANTES. [2]

Objectives: To compare the efficacy and safety of mapracorat with classical glucocorticoids used for the treatment of allergic skin diseases in dogs.
Animals: Six laboratory beagles.
The effect of mapracorat on lipopolysaccharide-induced TNFα secretion from canine peripheral blood derived mononuclear cells (PBMC) was tested. In vivo, mapracorat was compared to triamcinolone acetonide using a skin inflammation model. Skin fold thickness was determined after daily administration of mapracorat and triamcinolone acetonide over 14 days. [1]

[1]. The selective glucocorticoid receptor agonist mapracorat displays a favourable safety-efficacy ratio for the topical treatment of inflammatory skin diseases in dogs. Vet Dermatol. 2017 Feb; 28(1):46-e11.

[2]. Anti-allergic effects of mapracorat, a novel selective glucocorticoid receptor agonist, in human conjunctival fibroblasts and epithelial cells. Mol Vis. 2013 Jul 19:19:1515-25.

Mapracorat is a nonsteroidal selective glucocorticoid receptor agonist (SEGRA) with a hypothetical therapeutic index superior to traditional glucocorticoids. Mapracorat belongs to the aminoquinoline class of drugs. Mapracorat has been investigated for the treatment of eczema and atopic dermatitis. Objective: Glucocorticoids can both inhibit gene transcription (transcriptional repression) and activate gene transcription (transcriptional activation). The latter may lead to some side effects of these drugs. Mapracorat (also known as BOL-303242-X or ZK 245186) is a novel selective glucocorticoid receptor agonist that retains beneficial anti-inflammatory activity but appears to have weaker transcriptional activation, thus reducing the likelihood of side effects; it has been proposed for the topical treatment of inflammatory skin diseases. This study evaluated the anti-allergic activity of mapracorat at the ocular level and whether eosinophils and mast cells are its targets.
Methods: In vitro experiments were conducted using flow cytometry and Western blotting of caspase-3 fragments to assess apoptosis in human eosinophils. Transwell assays were used to evaluate the migration of eosinophils to platelet-activating factor. High-throughput Luminex multiplex chromatography was used to detect the expression and secretion of interleukin (IL)-6, IL-8, tumor necrosis factor-α (TNF-α), and chemokine (CC motif) ligand 5 (CCL5)/activated normal T cell regulatory factors (RANTES). Flow cytometry was used to detect annexin I and chemokine receptor CXC4 (CXCR4). In in vivo studies, allergic conjunctivitis was induced in ovalbumin-sensitized guinea pigs using an ocular allergen challenge test, and clinical scoring was used for evaluation. Conjunctival eosinophils were counted by microscopic examination or eosinophil peroxidase assay. Results: In cultured human eosinophils, mapracorat exhibited similar potency to dexamethasone, but showed greater efficacy in increasing spontaneous apoptosis and maintaining eosinophil survival with antagonistic cytokines. These effects were blocked by the glucocorticoid receptor antagonist mifepristone. Mapracorat's potency in inhibiting eosinophil migration and IL-8 release, as well as the inhibition of IL-6, IL-8, CCL5/RANTES, and TNF-α release from human mast cell lines, was comparable to dexamethasone. However, mapracorat's potency in inducing annexin I and CXCR4 expression on the surface of human eosinophils was significantly lower than that of dexamethasone; this is considered a possible marker of glucocorticoid-dependent transcriptional activation. In guinea pigs, both mapracorat and dexamethasone eye drops similarly alleviated the clinical symptoms of allergic conjunctivitis and conjunctival eosinophilic infiltration. Conclusion: Mapracorat shows promise as a candidate drug for the topical treatment of allergic eye diseases. It possesses anti-allergic properties similar to dexamethasone, but its transcriptional activating effect appears to be weaker compared to this classic glucocorticoid. Some of its cellular targets may contribute to eosinophil apoptosis and/or prevent their recruitment and activation, and inhibit the release of cytokines and chemokines. https://pubmed.ncbi.nlm.nih.gov/22194647/

C25H26F4N2O2

462.4886

462.193

C, 64.93; H, 5.67; F, 16.43; N, 6.06; O, 6.92

887375-26-0

(S)-Mapracorat;887375-15-7

24795088

Light yellow to yellow solid powder

5.763

2

8

6

33

675

1

CC1=NC2=C(C=C1)C(=CC=C2)NC[C@](CC(C)(C)C3=CC(=CC4=C3OCC4)F)(C(F)(F)F)O

VJGFOYBQOIPQFY-XMMPIXPASA-N

InChI=1S/C25H26F4N2O2/c1-15-7-8-18-20(5-4-6-21(18)31-15)30-14-24(32,25(27,28)29)13-23(2,3)19-12-17(26)11-16-9-10-33-22(16)19/h4-8,11-12,30,32H,9-10,13-14H2,1-3H3/t24-/m1/s1 SMILES

(2R)-1,1,1-trifluoro-4-(5-fluoro-2,3-dihydro-1-benzofuran-7-yl)-4-methyl-2-[[(2-methylquinolin-5-yl)amino]methyl]pentan-2-ol

ZK-245186; ZK 245186; Mapracorat; 887375-26-0; Mapracorat [USAN]; BOL303242X; ZK-245186; BOL303242-X; Mapracorat [USAN:INN]; ZK245186; BOL-303242; BOL303242; BOL 303242; BOL-303242-X; Mapracorat

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 : ≥ 33.6 mg/mL (~72.65 mM)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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