Substituted indoles as potent and orally active 5-lipoxygenase activating protein (FLAP) inhibitors

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.