MK-7246
目录号 : GC19395
A CRTH2/DP2 receptor antagonist
Cas No.:1218918-62-7
Sample solution is provided at 25 µL, 10mM.
;)
,-1-7$$$37316672.jpg');)
;)
;)
$$$36806353.jpg');)
;33(7)%EF%BC%9A546-561$$$37156877.jpg');)
;)
;)
;)
%201124-1138.$$$35908550.jpg');)
%20766-780.$$$37100057.jpg');)
%20418-432.$$$36893736.jpg');)
%EF%BC%9A-240-255.$$$35108512.jpg');)
533-545$$$36543525.jpg');)
%201-13.$$$36600053.jpg');)
;)
MK-7246 is a potent and selective CRTH2 antagonist with a Ki of 2.5±0.5 nM.
The affinity and selectivity of MK-7246 for human CRTH2 and recombinant human prostanoid receptors is determined by equilibrium competition analysis using the relevant radioligands and cell membranes expressing the various receptors. MK-7246 competes for [3H]PGD2 specific binding to cell membranes expressing recombinant human CRTH2 with high-affinity (Ki, 2.5 nM). MK-7246 displays a relatively high selectivity for CRTH2 with an affinity 149-fold lower for the DP receptor (Ki, 373±96 nM) and ≥1500-fold lower for the other prostanoid receptors (Ki, 7668±2169 nM for EP2, 3804±1290 nM for TP). MK-7246 is also tested in a panel of 157 enzyme and receptor assays at concentrations up to 100 uM and small but significant activity is detected only on phosphodiesterase 1 (PDE1, IC50=33.2 uM) and MAPK3 (ERK1, IC50=49.4 uM)[1].
Whether the inhibition of a clinically-relevant mechanism of allergic lung inflammation such as CRTH2 will lead to a suppression of inflammatory responses is investigated in A. alternata challenged Brown Norway rats (n=8 per group). Mast cell derived production of Prostaglandin D2 (PGD2) is believed to be a prime mediator of allergic inflammation. Since CRTH2 plays an important role in the early aspects of the allergic inflammation cascade, the effect of the CRTH2 antagonist is examined on A. alternate elicited pulmonary inflammatory responses. CRTH2 inhibitor MK-7246 is orally administered 1 h before and 23 h post-intratracheal instillation of the A. alternata. MK-7246 produces a dose dependent decrease in the number of eosinophils with a maximal inhibition of 74±5% in the 100 mg/kg group (P<0.05), IL-5 (80±12%) and IL-13 (76±14%) cytokines levels (P<0.05) [2].
References:
[1]. Gervais FG, et al. Pharmacological characterization of MK-7246, a potent and selective CRTH2 (chemoattractant receptor-homologous molecule expressed on T-helper type 2 cells) antagonist. Mol Pharmacol. 2011 Jan;79(1):69-76.
[2]. Gil MA, et al. Anti-inflammatory actions of Chemoattractant Receptor-homologous molecule expressed on Th2 by the antagonist MK-7246 in a novel rat model of Alternaria alternata elicited pulmonary inflammation. Eur J Pharmacol. 2014 Nov 15;743:106-16.
Kinase experiment: | The binding kinetics of [3H]MK-7246 (specific activity, 41 Ci/mmol) at human CRTH2 is characterized using recombinant HEK293E cell membranes. The radioligand binding experimental condition for CRTH2 as follows: the incubation mixture contains 10 mM MgCl2 instead of MnCl2, 10 nM [3H]MK-7246, and 1.25 μg of membrane protein. Total binding represents 10% of the radioligand adds to the incubation media, and specific binding at equilibrium corresponded to 85 to 95% of the total binding. The membranes are first incubated with [3H]MK-7246 for 120 min in the absence (total binding) or presence (nonspecific binding) of 10 μM MK-7246. To one series of total binding incubation tubes, 10 μM MK-7246 or 100 μM PGD2 is added to initiate dissociation of the radioligand from the receptor, and the reaction is left to proceed for up to 300 min. The samples are then harvested and processed as detailed above. The association and dissociation kinetic data analysis is done by nonlinear regression curve-fitting using Prism software to determine the observed on rate (Kobs) and dissociation rate (koff) constants, and t1/2 of on and off rates[1]. |
Animal experiment: | Rats[2]Intratracheal Budesonide is dosed 1 h prior to and 23 h post the A. alternate intratracheal dose while oral Budesonide (3 mg/kg) is administered 2 h before and 22 h post the A. alternata extract instillation. An intratracheally dosed Budesonide is prepared. MK-7246 (3, 10, 30 and 100 mg/kg) is administered orally 1 h before and 23 h post an A. alternata extract instillation in order to examine the effect of the CRTH2 antagonist on A. alternata elicited pulmonary inflammatory responses. Budesonide dosed orally is used as a positive control in both experiments. The animals are lightly anesthetized with 3% Isoflurane (supplemented with 100% oxygen), either 2 h following an oral dosing or 1 h following an intratracheal dosing. The animals are also secured on a rodent work stand to facilitate the localization of the larynx and tracheal openings. The microsprayer needle is inserted into the trachea and 0.1 mL of 10,000 μg/mL (total of 1000 μg) A. alternata extract is administered using a microsprayer. The animals are observed until they recover from anesthesia and then return to their cages and allow food and water ad libitum. |
References: [1]. Gervais FG, et al. Pharmacological characterization of MK-7246, a potent and selective CRTH2 (chemoattractant receptor-homologous molecule expressed on T-helper type 2 cells) antagonist. Mol Pharmacol. 2011 Jan;79(1):69-76. | |
| Cas No. | 1218918-62-7 | SDF | |
| Canonical SMILES | O=C(O)CC1=C(CC[C@@H](N(S(=O)(C2=CC=C(F)C=C2)=O)C)C3)N3C4=C1C=CC=C4 | ||
| 分子式 | C21H21FN2O4S | 分子量 | 416.47 |
| 溶解度 | DMSO : ≥ 250 mg/mL (600.28 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
||
| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
 |
1 mg | 5 mg | 10 mg |
| 1 mM | 2.4011 mL | 12.0057 mL | 24.0113 mL |
| 5 mM | 0.4802 mL | 2.4011 mL | 4.8023 mL |
| 10 mM | 0.2401 mL | 1.2006 mL | 2.4011 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Quality Control & SDS
- View current batch:
- Purity: >98.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet