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Structure-based design, synthesis, and biological evaluation of imidazo[1,2-b]pyridazine-based p38 MAP kinase inhibitors
Bioorganic & Medicinal Chemistry ( IF 3.5 ) Pub Date : 2017-12-24 , DOI: 10.1016/j.bmc.2017.12.031
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

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.



中文翻译:

基于咪唑并[1,2 - b ]哒嗪的p38 MAP激酶抑制剂的结构设计,合成及生物学评价

我们使用基于结构的设计策略确定了p38 MAP激酶的新型有效抑制剂。X射线晶体学表明,当p38MAP激酶与络合TAK-7151在共晶体结构),Phe169采用两种构象,其中,一个与相互作用1,而另一个示出了具有没有相互作用1。我们基于结构的设计策略表明,这两个构象通过增强的蛋白质-配体疏水相互作用融合为一个构象。根据该策略,我们专注于支架转化以鉴定咪唑并[1,2- b ]哒嗪衍生物作为p38 MAP激酶的有效抑制剂。在本文所述和评估的化合物中,N-氧化物16在人单核细胞THP-1细胞中显示出对p38 MAP激酶和LPS诱导的TNF-α产生的有效抑制作用,并且在大鼠胶原诱导的关节炎模型中具有显着的体内功效。在本文中,我们报告发现具有吡啶N-氧化物基团的有效,选择性和口服可生物利用的咪唑并[1,2 - b ]哒嗪基p38 MAP激酶抑制剂的发现。

更新日期:2017-12-24
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