NF-kB-inducing kinase (NIK) is a protein kinase central to the non-canonical NF-kB pathway and mediates the NF-kB signal through IKKa activation and p100 processing to nuclear transcription factors p52 and RelB. Inhibition of NIK could provide additional benefit over BAFF inhibition for the treatment of systemic lupus erythematosus (SLE) by blockade of the non-canonical NF-kB pathway through signal modulation of multiple receptors at once.<br/>Structure-based design efforts led to the identification of potent and selective NIK inhibitors spanning several chemical series. In one exceptionally cell potent subseries containing an imidazopyridine core, pursuing additional targets was laborious due to length of synthesis and lack of viable commercial intermediates. A general and efficient method for a metal-free one-pot synthesis of highly substituted fused imidazole-containing 5,5- and 5,6-fused bicyclic heterocycles was subsequently developed to allow further exploration of this series in a more rapid and concise manner.

Synthetic method development in the context of a medicinal program: The discovery of potent and selective inhibitors of NF-kB inducing kinase

256th National Meeting (2018)

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