Biological Activity
am679 is a topically applied and potent 5-lipoxygenase-activating protein (flap) inhibitor with an ic50 value of 2.2 nm [1] [2].flap and 5-lipoxygenase (5-lo) together convert membrane-derived arachidonic acid to the pro-inflammatory mediator leukotriene epoxide lta4. lta4 is hence rapidly converted into either ltb4 by lta4 hydrolase or ltc4 by ltc4 synthase [2].incubation with am679 for an extended time period (5 h) increased the potency of human blood against ltb4 production with an ic50 value of 53 nm. this time-dependent increase also happened with an ic50 value of 9 nm in rat blood incubated with am679 for 4 h [2].cysteinyl leukotrienes (cyslts) are known as promoters of inflammation and allergy. mouse eye infected by rsv began to show increased ocular cyslts 4 days after infection. am679 decreased the peak 6- to 8-day of ocular cyslts by more than 90%. by day 10, concentrations of cyslt for both am679-treated mouse eyes and control had almost returned to the baseline. a strong correlation between rsv and il-4 mrna had been found for human allergic conjunctivitis. 6 days after rsv infection, il-4 mrna concentrations were significantly elevated in rsv-infected mouse eyes. around 14 days, il-4 mrna concentrations were hence gradually decreased to near baseline. am679 could inhibit more than 80% of the il-4 increase resulted from rsv infection [1].
References
[1]. alla musiyenko, lucia correa, nicholas stock, et al. a novel 5-lipoxygenase-activating protein inhibitor, am679, reduces inflammation in the respiratory syncytial virus-infected mouse eye. clinical and vaccine immunology, 2009, 16(11):1654-1659.
[2]. nicholas stock, christopher baccei, gretchen bain, et al. 5-lipoxygenase-activating protein inhibitors. part 2: 3-{5-((s)-1-acetyl-2,3-dihydro-1h-indol-2-ylmethoxy)-3-tert-butylsulfanyl-1-[4-(5-methoxy-pyrimidin-2-yl)-benzyl]-1h-indol-2-yl}-2,2-dimethyl-propionic acid (am679)—a potent flap inhibitor. bioorganic & medicinal chemistry letters, 2010, 20:213-217.
