Pharmacology of montelukast sodium (Singulair™), a potent and selective leukotriene D4receptor antagonist

Abstract

Montelukast sodium (Singulair™), also known as MK-0476 (1-(((1(R)-(3-(2-(7-chloro-2-quinolinyl)-(E)-ethenyl)phenyl)(3-2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane) acetic acid sodium salt, is a potent and selective inhibitor of [3 H]leukotriene D 4 specific binding in guinea pig lung (K i 0.18 ± 0.03 nM), sheep lung (K i 4 nM), and dimethylsulfoxide-differentiated U937 cell plasma membrane preparations (K i 0.52 ± 0.23 nM), but it was essentially inactive versus [3 H]leukotriene C 4 specific binding in dimethylsulfoxide-differentiated U937 cell membranes (IC 50 10 μM) and [3 H]leukotriene B 4 specific binding in THP-1 cell membranes (IC 50 40 μM). Montelukast also inhibited specific binding of [3 H]leukotriene D 4 to guinea pig lung in the presence of human serum albumin, human plasma, and squirrel monkey plasma with K i values of 0.21 ± 0.08, 0.19 ± 0.02, and 0.26 ± 0.02 nM, respectively. Functionally, montelukast antagonized contractions of guinea pig trachea induced by leukotriene D 4(pA 2 value 9.3; slope 0.8). In contrast, montelukast (16 μM) failed to antagonize contractions of guinea pig trachea induced by leukotriene C 4(45 mM serine–borate), serotonin, acetylcholine, histamine, prostaglandin D 2, or U-44069. Intravenous montelukast antagonized bronchoconstriction induced in anesthetized guinea pigs by i.v. leukotriene D 4 but did not block bronchoconstriction to arachidonic acid, histamine, serotonin, or acetylcholine. Oral administration of montelukast blocked leukotriene D 4 induced bronchoconstriction in conscious squirrel monkeys, ovalbumin-induced bronchoconstriction in conscious sensitized rats (ED 50 0.03 ± 0.001 mg/kg; 4 h pretreatment), and also ascaris-induced early and late phase bronchoconstriction in conscious squirrel monkeys (0.03–0.1 mg/kg; 4 h pretreatment). A continuous i.v. infusion of montelukast (8 μg∙kg−1∙min−1) resulted in a 70% decrease in the peak early response and a 75% reduction of the late response to ascaris aerosol in allergic conscious sheep. Montelukast, a potent and selective leukotriene D 4 receptor antagonist with excellent in vivo activity is currently in clinical development for the treatment of asthma and related diseases.Key words: montelukast, MK-0476, Singulair™, leukotriene D 4 receptor antagonist, airway smooth muscle, antigen challenge.