Glucocorticoid receptor

Mapracorat 的 IC50 值为约 0.2 nM，并以浓度依赖性方式抑制活化的犬 PBMC 分泌 TNFα。
Mapracorat浓度依赖性地抑制激活犬PBMC的TNFα分泌，半数最大抑制浓度（IC50）值约为0.2 nmol/L。[1]

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Mapracorat在两种细胞类型中均以剂量依赖的方式显著降低IL-4或IL-13加TNF-α诱导的细胞因子释放和ICAM-1蛋白，其疗效与地塞米松相当。这些作用是通过糖皮质激素受体（GR）介导的，正如糖皮质激素受体表达沉默后抑制作用的逆转所证明的那样。 结论：这些体外模型的数据表明，mapracorat在减少IL-4或IL-13 + TNF-α-诱导的HConF和HConEpiC中过敏相关和促炎细胞因子的释放方面是有效和有效的，这支持了该化合物在减轻过敏性结膜炎过敏和炎症反应方面的临床评价。［2］

在 60 分钟的观察期间，皮内施用化合物 48/80（50 μg，溶于 50 μL 盐水）引起显着的风团和耀斑反应。与用丙酮处理的区域相比，Mapracorat (0.1%) 的局部预处理显着减少了风团和红斑反应。
皮下注射复方48/80 （50 μg， 50 μL生理盐水中），观察60 min后出现明显的轮状和光斑反应。局部预处理马普克拉特（0.1%）和曲安奈德（0.015%）与对照（丙酮）处理区域相比，显著降低了车轮和耀斑反应。然而，从第8天到第14天，每日一次局部使用曲安奈德可显著减少皮肤褶皱厚度，而马普科拉没有观察到这种减少。 结论 这些结果表明，在这些实验环境下，mapracorat具有与经典甾体糖皮质激素相当的抗炎功效，维持皮肤褶皱厚度表明，与同等浓度的曲安奈德相比，mapracorat具有更好的安全性。这进一步表明SEGRAs在狗的炎症性和瘙痒性皮肤病的治疗中显示出前景。[1]

目的：观察新型选择性糖皮质激素受体激动剂（SEGRA）对人结膜原代成纤维细胞和上皮细胞的抗过敏作用 方法：用白细胞介素-4 （IL-4）或IL-13 +肿瘤坏死因子-α (TNF-α)刺激人结膜上皮细胞（HConEpiC）和结膜成纤维细胞（HConF）两种原代人结膜细胞。Luminex技术被用于分析由此产生的炎症反应。然后测定mapracorat对eotaxin释放的影响以及对激活、正常T细胞表达和分泌（RANTES）、两种过敏相关趋化因子、促炎细胞因子和细胞间粘附分子1 （ICAM-1）的调节。使用小干扰RNA来确定mapracorat的作用是否通过糖皮质激素受体（GR）介导。以地塞米松为对照。

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) that is presumed to have a better therapeutic index compared to classical glucocorticoids.
Mapracorat is an aminoquinoline.
Mapracorat has been investigated for the treatment of Eczema and Atopic Dermatitis.

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Purpose: Glucocorticoids can either suppress gene transcription (transrepression) or activate it (transactivation). This latter process may contribute to certain side effects caused by these agents. Mapracorat (also known as BOL-303242-X or ZK 245186) is a novel selective glucocorticoid receptor agonist that maintains a beneficial anti-inflammatory activity but seems to be less effective in transactivation, resulting in a lower potential for side effects; it has been proposed for the topical treatment of inflammatory skin disorders. This study assessed the anti-allergic activity of mapracorat at the ocular level and whether eosinophils and mast cells are targets of its action.

Methods: With in vitro studies apoptosis was evaluated in human eosinophils by flow cytometry and western blot of caspase-3 fragments. Eosinophil migration toward platelet-activating factor was evaluated by transwell assays. Interleukin (IL)-6, IL-8, tumor necrosis factor-α (TNF-α), and the chemokine (C-C motif) ligand 5 (CCL5)/regulated upon activation normal T cell expressed, and presumably secreted (RANTES) were measured using a high-throughput multiplex luminex technology. Annexin I and the chemochine receptor C-X-C chemokine receptor 4 (CXCR4) were detected by flow cytometry. With in vivo studies, allergic conjunctivitis was induced in guinea pigs sensitized to ovalbumin by an ocular allergen challenge and evaluated by a clinical score. Conjunctival eosinophils were determined by microscopy or eosinophil peroxidase assay.

Results: In cultured human eosinophils, mapracorat showed the same potency as dexamethasone but displayed higher efficacy in increasing spontaneous apoptosis and in counteracting cytokine-sustained eosinophil survival. These effects were prevented by the glucocorticoid receptor antagonist mifepristone. Mapracorat inhibited eosinophil migration and IL-8 release from eosinophils or the release of IL-6, IL-8, CCL5/RANTES, and TNF-α from a human mast cell line with equal potency as dexamethasone, whereas it was clearly less potent than this glucocorticoid in inducing annexin I and CXCR4 expression on the human eosinophil surface; this was taken as a possible sign of glucocorticoid-dependent transactivation. In the guinea pig, mapracorat or dexamethasone eye drops induced an analogous reduction in clinical symptoms of allergic conjunctivitis and conjunctival eosinophil accumulation.

Conclusions: Mapracorat appears to be a promising candidate for the topical treatment of allergic eye disorders. It maintains an anti-allergic profile similar to that of dexamethasone but seems to have fewer transactivation effects in comparison to this classical glucocorticoid. Some of its cellular targets may contribute to eosinophil apoptosis and/or to preventing their recruitment and activation and to inhibiting 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

54.38

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)

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

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注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

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注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

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口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

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口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

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注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
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