Leukotrienes (LTs) play a critical role in both acute and chronic inflammation, and 5-lipoxygenase-activating protein (FLAP) is a key protein involved in leukotriene biosynthesis.  In the first step of the leukotriene synthesis FLAP, a nuclear membrane protein, selectively transfers arachidonic acid (AA) to the enzyme 5-lipoxygenase (5-LO) and facilitates the synthesis of leukotriene epoxide LTA4.  LTA4 is then converted to either LTB4 or LTC4. These LTs can activate G protein-coupled receptors including BLT1/BLT2 and CysLT1/CysLT2 leading to an immune response.  Inhibition of FLAP would prevent the biosynthesis of both LTB4 and LTC4 making it an attractive target for the treatment of asthma and other inflammatory diseases where LTs likely play a role.  Previous programs targeting the nuclear membrane protein FLAP have been hampered by the lack of potency, developability challenges, and the potential for drug-drug interactions (DDI). This presentation will describe a de novo approach to small molecule lead generation for the Janssen FLAP inhibitor program that led to novel substituted benzimidazoles.  Positive differentiation from known FLAP inhibitors and structure-activity relationships (SAR) for this series will be presented.

Discovery and synthesis of substituted benzimidazoles as 5-lipoxygenase-activating protein inhibitors for the treatment of inflammatory diseases

248th National Meeting (2014)

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