Pharmacology of montelukast sodium (Singulair™), a potent and selective leukotriene D4 receptor antagonist

摘要: 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 salt, is a potent and selective inhibitor of [3H]leukotriene D4 specific binding in guinea pig lung (Ki 0.18 +/- 0.03 nM), sheep 4 dimethylsulfoxide-differentiated U937 cell plasma membrane preparations 0.52 0.23 but it was essentially inactive versus C4 membranes (IC50 10 microM) B4 THP-1 40 microM). inhibited to the presence human serum albumin, plasma, squirrel monkey with Ki values 0.21 0.08, 0.19 0.02, 0.26 0.02 nM, respectively. Functionally, montelukast antagonized contractions trachea induced by leukotriene (pA2 value 9.3; slope 0.8). In contrast, (16 failed antagonize (45 mM serine-borate), serotonin, acetylcholine, histamine, prostaglandin D2, or U-44069. Intravenous bronchoconstriction anesthetized pigs i.v. did not block arachidonic acid, acetylcholine. Oral administration blocked conscious monkeys, ovalbumin-induced sensitized rats (ED50 0.001 mg/kg; h pretreatment), ascaris-induced early late phase monkeys (0.03-0.1 pretreatment). A continuous infusion (8 micrograms.kg-1.min-1) resulted 70% decrease peak response 75% reduction ascaris aerosol allergic sheep. Montelukast, receptor antagonist excellent vivo activity currently clinical development for treatment asthma related diseases.