AM679

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.