Discovery of 7-aminofuro[2,3-c]pyridine inhibitors of TAK1: Optimization of kinase selectivity and pharmacokinetics

HornbergerK.R.; ChenX.; CrewA.P.; KleinbergA.; MaL.; MulvihillM.J.; WangJ.; WildeV.L.; AlbertellaM.; BittnerM.; CookeA.; KadhimS.; KahlerJ.; MarescaP.; MayE.; MeynP.; RomashkoD.; TokarB.; TurtonR.

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Discovery of 7-aminofuro[2,3-c]pyridine inhibitors of TAK1: Optimization of kinase selectivity and pharmacokinetics

机译：TAK1的7-氨基呋喃[2,3-c]吡啶抑制剂的发现：激酶选择性和药代动力学的优化

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The kinase selectivity and pharmacokinetic optimization of a series of 7-aminofuro[2,3-c]pyridine inhibitors of TAK1 is described. The intersection of insights from molecular modeling, computational prediction of metabolic sites, and in vitro metabolite identification studies resulted in a simple and unique solution to both of these problems. These efforts culminated in the discovery of compound 13a, a potent, relatively selective inhibitor of TAK1 with good pharmacokinetic properties in mice, which was active in an in vivo model of ovarian cancer.

机译：描述了一系列TAK1的7-氨基呋喃[2,3-c]吡啶抑制剂的激酶选择性和药代动力学优化。来自分子建模，代谢位点的计算预测和体外代谢物鉴定研究的见解相交，为解决这两个问题提供了一种简单而独特的解决方案。这些努力最终导致了化合物13a的发现，该化合物是一种有效，相对选择性的TAK1抑制剂，在小鼠体内具有良好的药代动力学特性，在卵巢癌的体内模型中具有活性。

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《Bioorganic and Medicinal Chemistry Letters》 |2013年第16期|共6页
作者
HornbergerK.R.; ChenX.; CrewA.P.; KleinbergA.; MaL.; MulvihillM.J.; WangJ.; WildeV.L.; AlbertellaM.; BittnerM.; CookeA.; KadhimS.; KahlerJ.; MarescaP.; MayE.; MeynP.; RomashkoD.; TokarB.; TurtonR.;
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正文语种 eng
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7-Amino-furo2; 3-cpyridine; Cancer; Inflammation; Inhibitors; TAK1;

机译：7-氨基呋喃[2;3-c]吡啶;癌症;炎症;抑制剂;TAK1;

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1. Discovery of 7-aminofuro[2,3-c]pyridine inhibitors of TAK1: Optimization of kinase selectivity and pharmacokinetics [J] . HornbergerK.R., ChenX., CrewA.P., Bioorganic and Medicinal Chemistry Letters . 2013,第16期

机译：TAK1的7-氨基呋喃[2,3-c]吡啶抑制剂的发现：激酶选择性和药代动力学的优化
2. 3D QSAR modeling study on 7-aminofuro [2,3-c] pyridine derivatives as TAK1 inhibitors using CoMFA and COMSIA [J] . Balasubramanian Pavithra K., Balupuri Anand, Gadhe Changdev G., Medicinal chemistry research: an international journal for rapid communications on design and mechanisms of action of biologically active agents . 2015,第6期

机译：使用CoMFA和COMSIA对7-氨基呋喃[2,3-c]吡啶衍生物作为TAK1抑制剂进行3D QSAR建模研究
3. Discovery and optimization of novel pyridines as highly potent and selective glycogen synthase kinase 3 inhibitors [J] . Bioorganic and Medicinal Chemistry Letters . 2020,第4期

机译：新型吡啶的发现与优化高效和选择性糖原合酶激酶3抑制剂
4. CNX-774, an Irreversible, Selective and Orally Bioavailable Inhibitor of Bruton's Tyrosine Kinase: In Vitro ADME, Selectivity, and Pharmacokinetic Properties [C] . Prasoon Chaturvedi, Matthew Labenski, Erica Evans, American Society for Mass Spectrometry Conference on Mass Spectrometry and Allied Topics . 2011

机译：CNX-774，Bruton的酪氨酸激酶的不可逆转，选择性和口服生物可利用的抑制剂：体外Adme，选择性和药代动力学性能
5. Computer-aided discovery of novel natural product inhibitors of receptor tyrosine kinases and their rational semisynthetic optimizations for multiple malignancies control. [D] . Mohyeldin, Mohamed M. 2016

机译：计算机辅助发现的受体酪氨酸激酶的新型天然产物抑制剂及其对多种恶性肿瘤的合理的半合成优化。
6. Transforming Growth Factor β-activated Kinase 1 (TAK1) Kinase Adaptor TAK1-binding Protein 2 Plays Dual Roles in TAK1 Signaling by Recruiting Both an Activator and an Inhibitor of TAK1 Kinase in Tumor Necrosis Factor Signaling Pathway [O] . Peter Broglie, Kunihiro Matsumoto, Shizuo Akira, 2010

机译：转化生长因子β激活的激酶1（TAK1）激酶适配器TAK1结合蛋白2在肿瘤坏死因子信号通路中同时激活TAK1激酶的激活剂和抑制剂在TAK1信号传导中起双重作用。
7. Discovery and Pharmacokinetic and Pharmacological Properties of the Potent and Selective MET Kinase Inhibitor 1-{6-6-(4-Fluorophenyl)-1,2,4triazolo4,3-bpyridazin-3-ylsulfanylbenzothiazol-2-yl}-3-(2-morpholin-4-ylethyl)urea (SAR125844) [O] . Antonio Ugolini, Mireille Kenigsberg, Alexey Rak, 2016

机译：有效和选择性Met激酶抑制剂1- {6- 6-（4-氟苯基） - 1,2,4三唑类4,3-B Pyridazin-3- ylsulfanyl苯并噻唑苯二酚的发现和药物性能和药理性质-2-YL} -3-（2-晶啉-4-烯乙基）尿素（SAR125844）

Discovery of 7-aminofuro[2,3-c]pyridine inhibitors of TAK1: Optimization of kinase selectivity and pharmacokinetics

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