Aminopyridinecarboxamide-based inhaled IKK-2 inhibitors for asthma and COPD: Structure-activity relationship.
Xie J, Poda GI, Hu Y, Chen NX, Heier RF, Wolfson SG, Reding MT, Lennon PJ, Kurumbail RG, Selness SR, Li X, Kishore NN, Sommers CD, Christine L, Bonar SL, Venkatraman N, Mathialagan S, Brustkern SJ, Huang HC.
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).