After the body experiences an inflammatory stimulus, synthesis of the various pro-inflammatory leukotrienes is initiated. Increased leukotriene levels may contribute to the worsening of disease symptoms for various immune related pathologies, such as asthma. Interruption of portions of the leukotriene synthesis pathway have resulted in several marketed drugs for inflammatory diseases. 5-Lipoxygenase-activating protein (FLAP), a nuclear membrane protein, is a key constituent of the leukotriene synthesis cascade and is upstream of the enzymes responsible for the production of leukotriene A4 � leukotriene E4. FLAP inhibitors have shown proof of concept in allergen challenge studies, suggesting that FLAP inhibition could be a viable approach to treating asthma. Previous programs targeting FLAP have been hampered by a lack of human whole blood (hWB) potency, developability challenges, and the potential for drug-drug interactions (DDI). This presentation will describe a series of tetrasubstituted aryl aminopyrazines incorporating an ether linkage serving as the point of diversification. The potency, hWB activity, and pharmacokenetic properties were tunable through judicious selection of the ethereal substituent.  The chemistry, structure-activity relationships (SAR), cellular and in vivo activity for this series will be presented.

Discovery and synthesis of tetrasubstituted aryl aminopyrazines as potent 5-lipoxygenase-activating protein (FLAP) inhibitors

248th National Meeting (2014)

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