ABSTRACT
Installation of sites for metabolism in the lead compound PHA-767408 was the key focus of the IKK-2 inhaled program. This paper reports our efforts to identify a novel series of aminopyridinecarboxamide-based IKK-2 inhibitors, which display low nanomolar potency against IKK-2 with long duration of action (DOA), and metabolically labile to phase I and/or phase II metabolizing enzymes with potential capability for multiple routes of clearance. Several compounds have demonstrated their potential usefulness in the treatment of asthma and chronic obstructive pulmonary disease (COPD).
Subject(s)
Aminopyridines/chemical synthesis , Asthma/drug therapy , I-kappa B Kinase/antagonists & inhibitors , Niacinamide/analogs & derivatives , Protein Kinase Inhibitors/chemical synthesis , Pulmonary Disease, Chronic Obstructive/drug therapy , Pyrazoles/chemical synthesis , Administration, Inhalation , Aminopyridines/chemistry , Aminopyridines/pharmacology , Binding, Competitive , Drug Design , HEK293 Cells , Humans , Indazoles/chemistry , Indazoles/metabolism , Indazoles/pharmacology , Isonicotinic Acids/chemistry , Isonicotinic Acids/metabolism , Isonicotinic Acids/pharmacology , Microsomes, Liver/drug effects , Models, Molecular , Molecular Structure , Molecular Targeted Therapy , Niacinamide/chemical synthesis , Niacinamide/chemistry , Niacinamide/metabolism , Niacinamide/pharmacology , Phenethylamines/metabolism , Potassium Channel Blockers/metabolism , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyrazoles/chemistry , Pyrazoles/metabolism , Pyrazoles/pharmacology , Structure-Activity Relationship , Sulfonamides/metabolismABSTRACT
Series of aminopyridinecarboxamide-based inhibitors were synthesized and tested against human recombinant IKK-2 and in IL-1beta stimulated synovial fibroblasts. The 2-amino-5-chloropyridine-4-carboxamides were identified as the most potent inhibitors with improved cellular activity.
