Substituted 2,2-bisaryl-bicycloheptanes as novel and potent inhibitors of 5-lipoxygenase activating protein

The discovery and SAR of a novel series of substituted 2,2-bisaryl-bicycloheptane inhibitors of 5-lipoxygenase activating protein (FLAP) are herein described. SAR studies have shown that 2,5-substitution on the exo-aryl group is optimal for potency. The most potent compounds in this series have an ortho-nitrogen aryl linked with a methyleneoxy as the 5-substituent and a polar group such as a urethane as the 2-substituent. One of the most potent compounds identified is the 5-benzothiazolymethoxy-2-pyridinylcarbamate derivative 2 (FLAP IC50 = 2.8 nM) which blocks 89% of ragweed induced urinary LTE4 production in dogs (at an I.V. dose of 2.5 μg/kg/min). This compound inhibits calcium ionophore stimulated LTB4 production in both human polymorphonuclear (PMN) leukocytes and human whole blood (IC50 = 2.0 and 33 nM, respectively).

Graphical abstractThe discovery and SAR of a novel series of substituted 2,2-bisaryl-bicycloheptane inhibitors of 5-lipoxygense activating protein (FLAP) are herein described. One of the most potent compounds identified is compound 2 (FLAP IC50 = 2.8 nM) which blocks 89% of ragweed induced urinary LTE4 production in dogs (at an I.V. dose of 2.5 μg/kg/min). This compound inhibits calcium ionophore stimulated LTB4 production in both human polymorphonuclear (PMN) leukocytes and human whole blood (IC50 = 2.0 and 33 nM, respectively).Figure optionsDownload full-size imageDownload as PowerPoint slide