PHARMACOLOGY OF MONTELUKAST SODIUM (SINGULAIR(TM)), A POTENT AND SELECTIVE LEUKOTRIENE D-4 RECEPTOR ANTAGONIST

Montelukast sodium (Singulair(TM), 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 [H-3]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 [H-3]leukotriene C-4 specific binding in dimethylsulfoxide-differentiated U937 cell membranes (IC50 10 mu M) and [H-3]leukotriene B-4, specific binding in THP-1 cell membranes (IC50 40 mu M). Montelukast also inhibited specific binding of [H-3]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 mu M) 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 mu g . 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 Dq receptor antagonist with excellent in vivo activity is currently in clinical development for the treatment of asthma and related diseases.