Cysteinyl leukotrienes (cys-LTs) are lipid mediators of inflammation. The enzyme catalysing synthesis of cys-LTs, leukotriene C4 synthase (LTC4S), is considered an important drug target. The present study synthesized and characterized three tandem benzophenone amino pyridines as inhibitors of LTC4S. The molecules were potent and selective inhibitors of LTC4S with IC50 values of 95 - 124 nM. Molecular docking revealed binding in a hydrophobic crevice between two enzyme monomers and interaction with two catalytic residues, Arg104 and Arg31. The compounds potently inhibited cys-LT biosynthesis in immune cells. In co-incubations of platelets and polymorphonuclear leukocytes (PMNL), inhibition of LTC4S led to shunting of LTA4 towards anti-inflammatory lipoxin (LX) A4, which was significantly enhanced by simultaneous inhibition of LTA4H. Finally, in vivo, one compound reduced LTE4 levels in peritoneal lavage fluid by 88% and significantly decreases vascular permeability. The findings indicate that these compounds are valuable experimental tools in eicosanoid research.
See article at J Pharmacol Exp Ther 2015, 355:108-116.
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