Structure-based design, synthesis, and biological evaluation of imidazo[1, 2-b]pyridazine-based p38 MAP kinase inhibitors. Issue 3 (1st February 2018)

• Record Type: Journal Article
• Authors: Kaieda, Akira; Takahashi, Masashi; Takai, Takafumi; Goto, Masayuki; Miyazaki, Takahiro; Hori, Yuri; Unno, Satoko; Kawamoto, Tomohiro; Tanaka, Toshimasa; Itono, Sachiko; Takagi, Terufumi; Hamada, Teruki; Shirasaki, Mikio; Okada, Kengo; Snell, Gyorgy; Bragstad, Ken; Sang, Bi-Ching; Uchikawa, Osamu; Miwatashi, Seiji
• Is Part Of: Bioorganic & medicinal chemistry. Volume 26:Issue 3(2018)
• Page Start: 647
• Page End: 660
• Publication Date: 2018-02-01
• Subjects: 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 -- Imidazo[1, 2-b]pyridazine derivatives -- Pyridine N-oxide; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2017.12.031
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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.