Novel Tricyclic Inhibitors of IκB Kinase

The design and synthesis of a novel series of oxazole-, thiazole-, and imidazole-based inhibitors of I kappa B kinase (IKK) are reported. Biological activity was improved compared to the pyrazolopurine lead, and the expedient synthesis of the new tricyclic systems allowed for efficient exploration of structure-activity relationships. This, combined with an iterative rat cassette dosing strategy, was used to identify compounds with improved pharmacokinetic (PK) profiles to advance for in vivo evaluation.