The cysteinyl-leukotrienes (CysLTs), LTC4 and LTD4, are potent mediators of asthma and hypersensitivity. They induce bronchoconstriction, increase microvascular permeability, and are vasoconstrictors of coronary arteries. Their biological effects are transduced by a pair of G protein-coupled receptors, CysLT1 and CysLT2.1,2,3 Zafirlukast is a potent, selective CysLT1 receptor antagonist sold under the trade name Accolate for the treatment of asthma as well as for the symptoms associated with allergic rhinitis.4,5,6 It binds to the human CysLT1 and CysLT2 receptors with IC50 values of approximately 5 and 7,400 nM, respectively.1,2,3
1
Lynch, K.R., O'Neill, G.P., Liu, Q., et al. Characterization of the human cysteinyl leukotriene CysLT1 receptor. Nature399789-793(1999).
2
Heise, C.E., O'Dowd, B.F., Figueroa, D.J., et al. Characterization of the human cysteinyl leukotriene 2 receptor. J Biol Chem27530531-30536(2000).
3
Sarau, H.M., Ames, R.S., Chambers, J., et al. Identification, molecular cloning, expression, and characterization of a cysteinyl leukotriene receptor. Mol Pharmacol56657-663(1999).
4
Matassa, V.G., Maduskuie, T.P., Shapiro, H.S., et al. Evolution of a series of peptidoleukotriene antagonists: Synthesis and structure/activity relationships of 1,3,5-substituted indoles and indazoles. J Med Chem331781-1790(1990).
5
Silverman, R.A., Nowak, R.M., Korenblat, P.E., et al. Zafirlukast treatment for acute asthma. Evaluation in a randomized, double-blind, multicenter trail. Chest1261480-1489(2004).
6
Peters-Golden, M., and Henderson, W.R. The role of leukotrienes in allergic rhinitis. Ann Allergy Asthma Immunol94609-618(2005).
Heise, C.E., O'Dowd, B.F., Figueroa, D.J., et al. Characterization of the human cysteinyl leukotriene 2 receptor. J Biol Chem27530531-30536(2000).
Matassa, V.G., Maduskuie, T.P., Shapiro, H.S., et al. Evolution of a series of peptidoleukotriene antagonists: Synthesis and structure/activity relationships of 1,3,5-substituted indoles and indazoles. J Med Chem331781-1790(1990).
Peters-Golden, M., and Henderson, W.R. The role of leukotrienes in allergic rhinitis. Ann Allergy Asthma Immunol94609-618(2005).
Silverman, R.A., Nowak, R.M., Korenblat, P.E., et al. Zafirlukast treatment for acute asthma. Evaluation in a randomized, double-blind, multicenter trail. Chest1261480-1489(2004).
Lynch, K.R., O'Neill, G.P., Liu, Q., et al. Characterization of the human cysteinyl leukotriene CysLT1 receptor. Nature399789-793(1999).
Sarau, H.M., Ames, R.S., Chambers, J., et al. Identification, molecular cloning, expression, and characterization of a cysteinyl leukotriene receptor. Mol Pharmacol56657-663(1999).