Aminopyridinecarboxamide-based inhaled IKK-2 inhibitors for asthma and COPD: Structure-activity relationship.

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).

Aminopyridinecarboxamide-based inhibitors: Structure-activity relationship.

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.

Computer-Aided Design (CAD) of Synzymes: Use of Molecular Mechanics (MM) for the Rational Design of Superoxide Dismutase Mimics.

Mn(II) complexes of C-substituted macrocyclic 1,4,7,10,13-pentaazacyclopentadecane ligands have been shown to be excellent functional mimics (Synzymes) of the native enzyme manganese superoxide dismutase (Mn SOD). To better understand the profound effects that substituents exert on the SOD catalytic activity, we have utilized molecular mechanics (MM) calculations employing the CAChe system. Such a conformational analysis has made it possible to develop a consistent model that correlates catalytic rate with the ability of the ligand to adopt a folded geometry about the high-spin d(5) spherically symmetrical Mn(II) ion, thus affording a six-coordinate pseudo-octahedral geometry (the geometry required by Mn(III)).