tak-715 and Arthritis

We identified novel potent inhibitors of p38 MAP kinase using structure-based design strategy. X-ray crystallography showed that when p38 MAP kinase is complexed with TAK-715 (1) in a co-crystal structure, Phe169 adopts two conformations, where one interacts with 1 and the other shows no interaction with 1. Our structure-based design strategy shows that these two conformations converge into one via enhanced protein-ligand hydrophobic interactions. According to the strategy, we focused on scaffold transformation to identify imidazo[1,2-b]pyridazine derivatives as potent inhibitors of p38 MAP kinase. Among the herein described and evaluated compounds, N-oxide 16 exhibited potent inhibition of p38 MAP kinase and LPS-induced TNF-α production in human monocytic THP-1 cells, and significant in vivo efficacy in rat collagen-induced arthritis models. In this article, we report the discovery of potent, selective and orally bioavailable imidazo[1,2-b]pyridazine-based p38 MAP kinase inhibitors with pyridine N-oxide group.

Topics: Animals; Anti-Inflammatory Agents; Arthritis; Cell Line; Disease Models, Animal; Drug Design; Enzyme Activation; Female; Humans; Molecular Dynamics Simulation; Monocytes; p38 Mitogen-Activated Protein Kinases; Protein Kinase Inhibitors; Protein Structure, Tertiary; Pyridazines; Rats; Rats, Inbred Lew; Structure-Activity Relationship; Tumor Necrosis Factor-alpha