TK05
目录号 : GC65438TK05 是一种有效选择性的白三烯 C4 合成酶 (LTC4S) 抑制剂,其 IC50 值为 95 nM。
Cas No.:1245734-61-5
Sample solution is provided at 25 µL, 10mM.
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- Purity: >98.00%
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TK05 is a potent and selective inhibitor of leukotriene C4 synthase (LTC4S) with an IC50 of 95 nM[1].
TK05 reduces LTC4 production in a dose-dependent manner with an IC50 value of 318 ± 60 nM in MM6 Cells[1].
TK05 (0.12-6 mg/kg; given i.p.; only once) significantly reduces LTE4 levels[1].
[1]. Kleinschmidt TK, et al. Tandem Benzophenone Amino Pyridines, Potent and Selective Inhibitors of Human Leukotriene C4 Synthase. J Pharmacol Exp Ther. 2015 Oct;355(1):108-16.
Cas No. | 1245734-61-5 | SDF | Download SDF |
分子式 | C31H25ClN2O5 | 分子量 | 540.99 |
溶解度 | 储存条件 | Store at -20°C | |
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1 mg | 5 mg | 10 mg | |
1 mM | 1.8485 mL | 9.2423 mL | 18.4846 mL |
5 mM | 0.3697 mL | 1.8485 mL | 3.6969 mL |
10 mM | 0.1848 mL | 0.9242 mL | 1.8485 mL |
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Tandem Benzophenone Amino Pyridines, Potent and Selective Inhibitors of Human Leukotriene C4 Synthase
J Pharmacol Exp Ther 2015 Oct;355(1):108-16.PMID:26283693DOI:10.1124/jpet.115.227157.
Cysteinyl leukotrienes (cys-LTs) are lipid mediators of inflammation. The enzyme catalyzing synthesis of cys-LTs, leukotriene C4 synthase (LTC4S), is considered an important drug target. Here we report the synthesis and characterization of three tandem benzophenone amino pyridines as inhibitors of LTC4S in vitro and in vivo. The inhibitors were characterized in vitro using recombinant human LTC4S, MonoMac 6 cells, and a panel of peripheral human immune cells. In vivo, the compounds were tested in the Zymosan A-induced peritonitis mouse model. The molecules, denoted TK04, TK04a, and TK05, were potent and selective inhibitors of LTC4S with IC50 values of 116, 124, and 95 nM, respectively. Molecular docking revealed binding in a hydrophobic crevice between two enzyme monomers and interaction with two catalytic residues, Arg104 and Arg31. The TK compounds potently inhibited cys-LT biosynthesis in immune cells. In coincubations of platelets and polymorphonuclear leukocytes, inhibition of LTC4S led to shunting of LTA4 toward anti-inflammatory lipoxin A4, which was significantly enhanced by simultaneous inhibition of LTA4H. Finally, we found that TK05 (6 mg⋅kg(-1)⋅body weight) reduces LTE4 levels in peritoneal lavage fluid by 88% and significantly decreases vascular permeability in vivo. Our findings indicate that the TK compounds are valuable experimental tools in eicosanoid research in vitro and in vivo. Their chemical structures may serve as leads for further inhibitor design. Novel drugs depleting cys-LT production could be beneficial for treatment of inflammatory diseases associated with overexpression of LTC4S.