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  • RS 504393
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RS 504393

A CCR2 chemokine receptor antagonist

原价
¥1437-2637
价格
1150-2110
RS 504393的二维码

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  • 货号: ajci15220
  • CAS: 300816-15-3
  • 别名: 6-甲基-1,1'-[2-(5-甲基-2-苯基-4-恶唑基)乙基]-螺[4H-3-1,1-苯并恶嗪-4,4'-哌啶]-2(1H)-酮,RS-504393; RS504393
  • 分子式: C25H27N3O3
  • 分子量: 417.5
  • 纯度: >98%
  • 溶解度: DMF: 10 mg/ml,DMF:PBS (pH 7.2) (1:9): 0.1 mg/ml,DMSO: 1 mg/ml,Ethanol: Slightly Soluble
  • 储存: Store at -20°C
  • 库存: 现货

Background

RS 504393 is a selective CCR2 chemokine receptor antagonist (IC50 values are 89 nM and > 100 μM for inhibition of human recombinant CCR2 and CCR1 receptors respectively).


RS 504393 inhibits the MCP-1-induced chemotaxis with an IC50 of 330 nM. RS 504393 treatment suppresses allergen induced β-hexosaminidase release significantly. Without allergen priming, MCP-1 induces mast cell degranulation, which is completely suppressed by RS 504393[4].


RS504393 (0.3-3 μg) with CCL2 progressively blocks thermal hyperalgesia dose-dependently in mice[1]. RS 504393 (5?mg/kg, i.v.) supresses the elevated numbers of leukocytes and increased total protein content in BALF induced by The LPS. RS504393 significantly down regulates the LPS-induced elevation of IL-1β, PAI-1 mRNA and protein expressions. RS504393 significantly suppresses induced lung edema, protein-rich fluid, polymorphonuclear accumulation and bronchial wall thickening induced by LPS[2]. RS-504393 significantly reduces renal pathology, especially the extensive interstitial fibrosis mediated by decrease in type I collagen synthesis in a UUO model[3].


参考文献:
[1]. Baamonde, Ana., et al. Involvement of glutamate NMDA and AMPA receptors, glial cells and IL-1β in the spinal hyperalgesia evoked by the chemokine CCL2 in mice. Neuroscience Letters (2011), 502(3), 178-181.
[2]. Yang, Dong., et al. Roles of CC chemokine receptors (CCRs) on lipopolysaccharide-induced acute lung injury. Respiratory Physiology & Neurobiology (2010), 170(3), 253-259.
[3]. Kitagawa, Kiyoki., et al. Blockade of CCR2 ameliorates progressive fibrosis in kidney. American Journal of Pathology (2004), 165(1), 237-246.
[4]. Tominaga T, et al. Blocking mast cell-mediated type I hypersensitivity in experimental allergic conjunctivitis by monocyte chemoattractant protein-1/CCR2. Invest Ophthalmol Vis Sci. 2009 Nov;50(11):5181-8.
[5]. Mirzadegan T, et al. Identification of the binding site for a novel class of CCR2b chemokine receptor antagonists: binding to a common chemokine receptor motif within the helical bundle. J Biol Chem. 2000 Aug 18;275(33):25562-71.

Protocol

Kinase experiment:

Isolated mast cells are sensitized by incubation with anti-DNP IgE in RPMI1640 containing 10 ng/mL of murine recombinant IL-3, 10 ng/mL of recombinant SCF, and 5% murine serum. The cells are then washed with HBSS containing 10 ng/mL of murine recombinant IL-3, 10 ng/mL of recombinant SCF, 0.04% BSA, and 10 mM HEPES. Resuspended cells at a concentration of 2 to 8×104?cells/100 μL are transferred into triplicate wells of a 96 well U-bottom plate and allowed to equilibrate at 37°C for 10 minutes before the addition of DNP-albumin or compound 48/80. After 45 minutes, the plate is centrifuged at 290 g?for 5 minutes at 4°C. The β-hexosaminidase activity of the culture supernatant is determined using a Published protocol. Fifty-μL aliquots of the supernatant are placed in wells of another 96-well plate together with 100 μL of 2.5 mM?p-nitrophenyl-N-acetyl β-d?glucosaminide solubilized in 0.04mol/Lcitrate buffer adjusted to pH 4.5 with disodium phosphate. After incubation at 37°C for 90 minutes, the reactions are terminated by addition of 50 μL of 0.4mol/Lglycin adjusted to pH 10.7 with sodium hydroxide. The colored product is measured at 405 nm with a reference filter of 570 nm. The relative release of β-hexosaminidase is defined as the activity in the supernatant of the tested cells divided by the activity in the positive control cell supernatant, multiplied by 100. Compound 48/80 stimulus is used for assay control.

Animal experiment:

Male C57BL/6J mice (n=30) and male homozygote CCR1, CCR2 and CCR3 knockout mice (n=12, in each phenotype), 6-8 weeks old and weighing 20±2?g. Intranasal administration of PBS or LPS (5?mg/kg) is performed in a volume of 1?mL/kg body weight. C57BL/6J mice are treated with vehicle or RS504393 (5?mg/kg) intraperitoneally 30?min before LPS challenge. Four hours after LPS challenge, mice are terminated by an intraperitoneal injection of an overdose of pentobarbitone. The mice are kept on a 12-h light/dark cycle with access to mice chow and water?ad libitum.

参考文献:

[1]. Baamonde, Ana., et al. Involvement of glutamate NMDA and AMPA receptors, glial cells and IL-1β in the spinal hyperalgesia evoked by the chemokine CCL2 in mice. Neuroscience Letters (2011), 502(3), 178-181.
[2]. Yang, Dong., et al. Roles of CC chemokine receptors (CCRs) on lipopolysaccharide-induced acute lung injury. Respiratory Physiology & Neurobiology (2010), 170(3), 253-259.
[3]. Kitagawa, Kiyoki., et al. Blockade of CCR2 ameliorates progressive fibrosis in kidney. American Journal of Pathology (2004), 165(1), 237-246.
[4]. Tominaga T, et al. Blocking mast cell-mediated type I hypersensitivity in experimental allergic conjunctivitis by monocyte chemoattractant protein-1/CCR2. Invest Ophthalmol Vis Sci. 2009 Nov;50(11):5181-8.
[5]. Mirzadegan T, et al. Identification of the binding site for a novel class of CCR2b chemokine receptor antagonists: binding to a common chemokine receptor motif within the helical bundle. J Biol Chem. 2000 Aug 18;275(33):25562-71.

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