Download MendeleyStructure-based design, synthesis, and biological evaluation of imidazo[1,2-b]pyridazine-based p38 MAP kinase inhibitors.
Kaieda, A., Takahashi, M., Takai, T., Goto, M., Miyazaki, T., Hori, Y., Unno, S., Kawamoto, T., Tanaka, T., Itono, S., Takagi, T., Hamada, T., Shirasaki, M., Okada, K., Snell, G., Bragstad, K., Sang, B.C., Uchikawa, O., Miwatashi, S.(2018) Bioorg Med Chem 26: 647-660
- PubMed: 29291937
- DOI: https://doi.org/10.1016/j.bmc.2017.12.031
- Primary Citation of Related Structures:
5WJJ, 6ANL - PubMed Abstract:
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.
Organizational Affiliation:
Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: [email protected].
