Author/Authors :
Richard Frenette، نويسنده , , John H. Hutchinson، نويسنده , , Serge Léger، نويسنده , , Michel Thérien، نويسنده , , Christine Brideau، نويسنده , , Chi C. Chan، نويسنده , , Stella Charleson، نويسنده , , Diane Ethier، نويسنده , , Jocelyne Guay، نويسنده , , Tom R. Jones، نويسنده , , Malia McAuliffe، نويسنده , , Hanna Piechuta، نويسنده , , Denis Riendeau، نويسنده , , Philip Tagari، نويسنده , , Jean-Yves Girard، نويسنده ,
Abstract :
This paper reports on the SAR investigation of inhibitors of 5-lipoxygenase activating protein (FLAP) based on MK-0591. Emphasis was made on modifications to the nature of the link between the indole and the quinoline moieties, to the substitution pattern around the two heterocycles and to possible replacements of the quinoline moiety. Lead optimization culminated in (3-[1-(4-chlorobenzyl)-3-(t-butylthio)-5-(pyridin-2-ylmethoxy)-indol-2-yl]-2,2-dimethylpropanoic acid (18k), as a potent inhibitor of leukotriene biosynthesis that is well absorbed and active in functional models.
This paper reports on the SAR investigation of inhibitors of 5-lipoxygenase activating protein (FLAP) based on MK-0591. Emphasis was made on modifications to the nature of the link between the indole and the quinoline moieties, to the substitution pattern around the two heterocycles and to possible replacements of the quinoline moiety. A potent inhibitor, which is well absorbed and active in functional models, was identified.
