Structure-based design,synthesis, and biological evaluation of imidazo[1,2-b]pyridazine-based p38 MAP kinase inhibitors |
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Authors: | Akira Kaieda Masashi Takahashi Takafumi Takai Masayuki Goto Takahiro Miyazaki Yuri Hori Satoko Unno Tomohiro Kawamoto Toshimasa Tanaka Sachiko Itono Terufumi Takagi Teruki Hamada Mikio Shirasaki Kengo Okada Gyorgy Snell Ken Bragstad Bi-Ching Sang Osamu Uchikawa Seiji Miwatashi |
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Institution: | 1. Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan;2. Takeda California, 10410 Science Center Drive, San Diego, CA 92121, United States |
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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 imidazo1,2-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 imidazo1,2-b]pyridazine-based p38 MAP kinase inhibitors with pyridine N-oxide group. |
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Keywords: | MAP mitogen-activated protein TNF-α tumor necrosis factor-α IL-1β interleukin-1β RA rheumatoid arthritis IBD inflammatory bowel disease COPD chronic obstructive pulmonary disease LPS lipopolysaccharide DMPK drug metabolism and pharmacokinetics CIA collagen-induced arthritis SAR structure-activity relationships P38 mitogen-activated protein kinase inhibitors Rheumatoid arthritis Structure-based design Corresponding author |
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