ABSTRACT
A potent and selective series of 2-amino-3,5-diarylbenzamide inhibitors of IKK-alpha and IKK-beta is described. The most potent compounds are 8h, 8r and 8v, with IKK-beta inhibitory potencies of pIC(50) 7.0, 6.8 and 6.8, respectively. The series has excellent selectivity, both within the IKK family over IKK-epsilon, and across a wide variety of kinase assays. The potency of 8h in the IKK-beta enzyme assay translates to significant cellular activity (pIC(50) 5.7-6.1) in assays of functional and mechanistic relevance.
Subject(s)
Benzamides/pharmacology , Enzyme Inhibitors/pharmacology , I-kappa B Kinase/antagonists & inhibitors , Benzamides/chemistry , Enzyme Inhibitors/chemistry , Hydrogen Bonding , Models, MolecularABSTRACT
The identification and hit-to-lead exploration of a novel, potent and selective series of substituted benzimidazole-thiophene carbonitrile inhibitors of IKK-epsilon kinase is described. Compound 12e was identified with an IKK-epsilon enzyme potency of pIC(50) 7.4, and has a highly encouraging wider selectivity profile, including selectivity within the IKK kinase family.