Identification and study of new NF-κB-inducing kinase ligands derived from the imidazolone scaffold.

Chronic kidney disease (CKD) is a growing health concern, projected to be a major cause of death by 2040, due to an increasing risk of acute kidney injury (AKI). Systems biology-derived data suggest that the unmet need for an orally available drug to treat AKI and improve CKD outcomes may be addressed by targeting kidney inflammation and, specifically, nuclear factor κB-inducing kinase (NIK), a key signaling molecule that activates the noncanonical nuclear factor κB (NF-κB) pathway. We have prepared and identified a small family of imidazolone derivatives that bind NIK and inhibit the noncanonical NF-κB activation pathway.

1,2,3-Benzotriazine Synthesis by Heterocyclization of -Tosylmethyl Isocyanide Derivatives.

An efficient methodology to form 4-alkoxy- and 4-aryloxybenzo[][1,2,3]triazines via an intramolecular heterocyclization of 1-azido-2-[isocyano(-tosyl)methyl]benzenes under basic conditions has been developed. DFT calculations have been performed to further understand the mechanism of this heterocyclization, which occurs in good to excellent yields with a broad scope.