Discovery Of Mk-0476, A Potent And Orally-Active Leukotriene D-4 Receptor Antagonist Devoid Of Peroxisomal Enzyme-Induction

Structure-activity studies leading to the discovery of 1 (MK-0476) are described. The initial compound of this series, 2, was a potent leukotriene D-4 (LTD(4)) antagonist, but was also a peroxisomal enzyme inducer in the mouse. Structure-activity relationships around the thioether chain were explored to remove this undesirable feature. It was found that alkyl substituents in the beta position relative to the carboxylic acid reduce the potency as a peroxisomal enzyme inducer while preserving the LTD(4) antagonistic properties. Dialkyl substitution essentially eliminates the enzyme induction. The optimal styryl quinoline 1 exhibited high in vitro potency and in vivo activity on oral dosing without significant liver enzyme induction in the mouse.