Novel Tricyclic Inhibitors of IκB Kinase

The design and synthesis of a novel series of oxazole-, thiazole-, and imidazole-based inhibitors of IκB 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.