Author/Authors :
M. Labelle، نويسنده , , M. Belley، نويسنده , , Y. Gareau، نويسنده , , J. Y. Gauthier، نويسنده , , D. Guay and R. Schulz، نويسنده , , R. Gordon، نويسنده , , S. G. Grossman، نويسنده , , T. R. Jones، نويسنده , , Y. Leblanc، نويسنده , , M. McAuliffe، نويسنده , , C. McFarlane، نويسنده , , P. Masson، نويسنده , , K. M. Metters، نويسنده , , N. Ouimet، نويسنده , , D. H. Patrick، نويسنده , , H. Piechuta، نويسنده , , C. Rochette، نويسنده , , N. Sawyer، نويسنده , , Y. B. Xiang، نويسنده , , C. B. Pickett، نويسنده , , et al.، نويسنده ,
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 D4 (LTD4) 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 ß position relative to the carboxylic acid reduce the potency as a peroxisomal enzyme inducer while preserving the LTD4 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.
