Zileuton (Synonyms: A 64077)

IC50: Zileuton inhibited 5-hydroxyeicosatetraenoic aicd synthesis in rat basophilic leukemia cell and polymorphonuclear leukocytes (IC50 = 0.5 and 0.3 μM), respectively [1].
5-Lipoxygenase pathway is to form leukotrienes, including leukotriene B4 (LTB4), 5-oxo-6E,8Z,11Z,14Z-eicosatetranoic acid and the cysteinyl leukotrienes (LTC4, LTD4 and LTE4) and activates all four leukotriene receptors, BLT1, BLT2, cysLT1 and cysLT2. Zileuton is the only commercially available inhibitor of the 5-Lipoxygenase pathway.
In vitro: Treatment of H9c2 cells with zileuton efficiently induced COX-2 expression and PGE2 biosynthesis in a time- and dose-dependent manner. Zileuton also exerted a profound protective effect against H2O2-induced oxidative stress, a mimic of reperfusion damage in vitro, and this protective effect was abolished by COX-2-selective inhibitor. Furthermore, zileuton-stimulated ERK1/2 and Akt phosphorylation was attenuated by rottlerin, indicating that PKCδ might act upstream of ERK1/2 and Akt. These results suggest that zileuton-induced COX-2 expression is sequentially mediated through PKCδ-dependent activation of ERK1/2 and Akt. Based on these findings, we propose that zileuton might provide a new therapeutic strategy for ischemia/reperfusion injury of the heart [2].
In vivo: To investigate the mechanism underlying zileuton's neuroprotection, SD rats underwent permanent middle cerebral artery occlusion (MCAO), then received treatment with zileuton or vehicle after the onset of ischemia. Zileuton was found to significantly reduce neurological deficit scores, cerebral infarct volume, MPO activity, and the lipid peroxidation levels. It also inhibited the expression of NF-kappaB and decreased the expression and activity of iNOS in rat brain. In addition, zileuton attenuated the release of TNF-alpha and IL-1beta in serum. These results suggested that zileuton reduces inflammatory reaction and brain damage in a rat model of permanent focal cerebral ischemia. The neuroprotective effect of zileuton in cerebral ischemia might be associated with the inhibition of inflammatory reaction [3].
Clinical trial:
Zileuton (trade name ZYFLO) is an orally active inhibitor of 5-lipoxygenase, and thus inhibits leukotrienes (LTB4, LTC4, LTD4, and LTE4) formation. Zileuton is used for the maintenance treatment of asthma. Zileuton was introduced in 1996 by Abbott Laboratories and is now marketed in two formulations by Cornerstone Therapeutics Inc. under the brand names ZYFLO and ZYFLO CR. Given the important role that leukotrienes play in airway inflammation, zileuton provides an additional therapeutic option in the management of chronic, persistent asthma, particularly those asthmatics with more severe disease. In addition, zileuton has shown promise in a number of other conditions, including upper airway inflammatory conditions, dermatological disease and chronic obstructive pulmonary disease. The development of new formulations, including a controlled release tablet formulation for b.i.d. dosing and an intravenous preparation for acute asthma exacerbations may enhance clinical utility and expand therapeutic indications.
Reference:
[1] Carter GW, Young PR, Albert DH, Bouska J, Dyer R, Bell RL, Summers JB, Brooks DW. 5-lipoxygenase inhibitory activity of zileuton. J Pharmacol Exp Ther. 1991;256(3):929-37.
[2] Hyun-Jeong Kwak, Kyoung-Mi Park, Hye-Eun Choi, Hyun-Joung Lim, Jin-Hee Park, Hyun-Young Park. The cardioprotective effects of zileuton, a 5-lipoxygenase inhibitor, are mediated by COX-2 via activation of PKCδ. Cellular Signalling 22 (2010) 80-87
[3] Tu XK, Yang WZ, Wang CH, Shi SS, Zhang YL, Chen CM, Yang YK, Jin CD, Wen S.Zileuton reduces inflammatory reaction and brain damage following permanent cerebral ischemia in rats. Inflammation. 2010;33(5):344-52.