The antagonists but not partial agonists of glucocorticoid receptor ligands show substantial side effect dissociation.

A synthetic glucocorticoid receptor (GR) ligand with the efficacy of a glucocorticoid, but without the accompanying side effects, would meet an unmet medical need for the treatment of inflammatory diseases. It was hypothesized that a GR ligand that shifted helix 12 in a manner distinct from an agonist and an antagonist would confer a distinct GR conformation, resulting in differential gene expression and, ultimately, dissociation of antiinflammatory activity from side effects. A structural feature expected to interfere with helix 12 was incorporated into a nonsteroidal, tricyclic scaffold to create novel, high-affinity, and selective GR ligands that manifested a dual function in cellular assays, partial but robust agonist activity for inflammatory cytokine inhibition, and full antagonist activity for reporter gene activation.

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.

Inhibition of IKK-2 by 2-[(aminocarbonyl)amino]-5-acetylenyl-3-thiophenecarboxamides.

A series of 21 novel 2-[(aminocarbonyl)amino]-5-acetylenyl-3-thiophenecarboxamides were synthesized and evaluated for the inhibition of IKK-2. In spite of their often modest activity on the enzyme, six selected analogs showed significant inhibition of the production of inflammatory cytokine IL-8 in IL-1beta stimulated rheumatoid arthritis-derived synovial fibroblasts, demonstrating their potential usefulness as NF-kappaB regulators.

IKK-i and TBK-1 are enzymatically distinct from the homologous enzyme IKK-2: comparative analysis of recombinant human IKK-i, TBK-1, and IKK-2.

NF-kappaB is sequestered in the cytoplasm by the inhibitory IkappaB proteins. Stimulation of cells by agonists leads to the rapid phosphorylation of IkappaBs leading to their degradation that results in NF-kappaB activation. IKK-1 and IKK-2 are two direct IkappaB kinases.