MK-7246 - Prostaglandin Receptor Antagonist - 生命科學(xué)試劑 - MedChemExpress

1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemEMK-7246Cat. No.: HY-15853CAS No.: 1218918-62-7分式: CHFNOS分量: 416.47作靶點(diǎn): Prostaglandin Receptor作通路: GPCR/G Protein儲(chǔ)存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 month溶解性數(shù)據(jù)體外實(shí)驗(yàn) DMSO : 250 mg/mL (600.28 mM)* means

2、soluble, but saturation unknown.Mass Solvent1 mg 5 mg 10 mg Concentration制備儲(chǔ)備液1 mM 2.4011 mL 12.0057 mL 24.0113 mL5 mM 0.4802 mL 2.4011 mL 4.8023 mL10 mM 0.2401 mL 1.2006 mL 2.4011 mL請根據(jù)產(chǎn)品在不同溶劑中的溶解度，選擇合適的溶劑配制儲(chǔ)備液，并請注意儲(chǔ)備液的保存式和期限。BIOLOGICAL ACTIVITY物活性 MK-7246種有效的選擇性 CRTH2 拮抗劑，Ki 值為 2.50.5 nM。IC50 & Ta

3、rget CRTH2/DP2 Receptor TP EP22.5 nM (Ki) 3804 nM (Ki) 7668 nM (Ki)體外研究The affinity and selectivity of MK-7246 for human CRTH2 and recombinant human prostanoid receptors is1/3 Master of Small Molecules 您邊的抑制劑師www.MedChemEdetermined by equilibrium competition analysis using the relevant radioligands

4、and cell membranesexpressing the various receptors. MK-7246 competes for 3HPGD2 specific binding to cell membranesexpressing recombinant human CRTH2 with high-affinity (Ki, 2.5 nM). MK-7246 displays a relatively highselectivity for CRTH2 with an affinity 149-fold lower for the DP receptor (Ki, 37396

5、 nM) and 1500-fold lowerfor the other prostanoid receptors (Ki, 76682169 nM for EP2, 38041290 nM for TP). MK-7246 is alsotested in a panel of 157 enzyme and receptor assays at concentrations up to 100 M and small butsignificant activity is detected only on phosphodiesterase 1 (PDE1, IC50=33.2 M) and

6、 MAPK3 (ERK1,IC50=49.4 M) 1.體內(nèi)研究 Whether the inhibition of a clinically-relevant mechanism of allergic lung inflammation such as CRTH2 willlead to a suppression of inflammatory responses is investigated in A. alternata challenged Brown Norwayrats (n=8 per group). Mast cell derived production of Pros

7、taglandin D2 (PGD2) is believed to be a primemediator of allergic inflammation. Since CRTH2 plays an important role in the early aspects of the allergicinflammation cascade, the effect of the CRTH2 antagonist is examined on A. alternate elicited pulmonaryinflammatory responses. CRTH2 inhibitor MK-72

8、46 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 ofeosinophils with a maximal inhibition of 745% in the 100 mg/kg group (P 2.PROTOCOLKinase Assay 1 The binding kinetics of 3HMK-7246 (specific a

9、ctivity, 41 Ci/mmol) at human CRTH2 is characterized usingrecombinant HEK293E cell membranes. The radioligand binding experimental condition for CRTH2 asfollows: the incubation mixture contains 10 mM MgCl2 instead of MnCl2, 10 nM 3HMK-7246, and 1.25 g ofmembrane protein. Total binding represents 10%

10、 of the radioligand adds to the incubation media, andspecific binding at equilibrium corresponded to 85 to 95% of the total binding. The membranes are firstincubated with 3HMK-7246 for 120 min in the absence (total binding) or presence (nonspecific binding) of10 M MK-7246. To one series of total bin

11、ding incubation tubes, 10 M MK-7246 or 100 M PGD2 is addedto initiate dissociation of the radioligand from the receptor, and the reaction is left to proceed for up to 300min. The samples are then harvested and processed as detailed above. The association and dissociationkinetic data analysis is done

12、 by nonlinear regression curve-fitting using Prism software to determine theobserved on rate (Kobs) and dissociation rate (koff) constants, and t1/2 of on and off rates 1.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Animal Rats 2Administration 2 Intr

13、atracheal Budesonide is dosed 1 h prior to and 23 h post the A. alternate intratracheal dose while oralBudesonide (3 mg/kg) is administered 2 h before and 22 h post the A. alternata extract instillation. Anintratracheally dosed Budesonide is prepared. MK-7246 (3, 10, 30 and 100 mg/kg) is administere

14、d orally 1 hbefore and 23 h post an A. alternata extract instillation in order to examine the effect of the CRTH2antagonist on A. alternata elicited pulmonary inflammatory responses. Budesonide dosed orally is used as apositive control in both experiments. The animals are lightly anesthetized with 3

15、% Isoflurane (supplementedwith 100% oxygen), either 2 h following an oral dosing or 1 h following an intratracheal dosing. The animalsare also secured on a rodent work stand to facilitate the localization of the larynx and tracheal openings. Themicrosprayer needle is inserted into the trachea and 0.

16、1 mL of 10,000 g/mL (total of 1000 g) A. alternata2/3 Master of Small Molecules 您邊的抑制劑師www.MedChemEextract is administered using a microsprayer. The animals are observed until they recover from anesthesiaand then return to their cages and allow food and water ad libitum.MCE has not independently con

17、firmed the accuracy of these methods. They are for reference only.REFERENCES1. Gervais FG, et al. Pharmacological characterization of MK-7246, a potent and selective CRTH2 (chemoattractant receptor-homologousmolecule 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 elicite