Discovery of MK-0476, a potent and orally active leukotriene D4 receptor antagonist devoid of peroxisomal enxyme induction
1995
Abstract 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 s 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.
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