Furo[3,2-b]pyridine: A Privileged Scaffold for Highly Selective Kinase Inhibitors and Effective Modulators of the Hedgehog Pathway.,Angewandte Chemie International Edition

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Furo[3,2-b]pyridine: A Privileged Scaffold for Highly Selective Kinase Inhibitors and Effective Modulators of the Hedgehog Pathway.
Angewandte Chemie International Edition ( IF 16.1 ) Pub Date : 2018-12-20 , DOI: 10.1002/anie.201810312
Václav Němec _{1,

2} , Michaela Hylsová _{1,

2} , Lukáš Maier _{1,

2} , Jana Flegel ₃ , Sonja Sievers ₃ , Slava Ziegler ₃ , Martin Schröder ₄ , Benedict-Tilman Berger ₄ , Apirat Chaikuad ₄ , Barbora Valčíková _{2,

5} , Stjepan Uldrijan _{2,

5} , Stanislav Drápela _{2,

6} , Karel Souček _{2,

6} , Herbert Waldmann ₃ , Stefan Knapp ₄ , Kamil Paruch _{1,

2}

Affiliation

Reported is the identification of the furo[3,2‐b]pyridine core as a novel scaffold for potent and highly selective inhibitors of cdc‐like kinases (CLKs) and efficient modulators of the Hedgehog signaling pathway. Initially, a diverse target compound set was prepared by synthetic sequences based on chemoselective metal‐mediated couplings, including assembly of the furo[3,2‐b]pyridine scaffold by copper‐mediated oxidative cyclization. Optimization of the subseries containing 3,5‐disubstituted furo[3,2‐b]pyridines afforded potent, cell‐active, and highly selective inhibitors of CLKs. Profiling of the kinase‐inactive subset of 3,5,7‐trisubstituted furo[3,2‐b]pyridines revealed sub‐micromolar modulators of the Hedgehog pathway.

中文翻译：

呋喃[3,2-b]吡啶：一种用于高选择性激酶抑制剂和刺猬通路有效调节剂的特权支架。

据报道，呋喃[3,2-b]吡啶核是一种新型的支架，可作为有效且高度选择性的cdc-like激酶（CLKs）抑制剂和刺猬信号通路的有效调节剂。最初，基于化学选择性金属介导的偶联，通过合成序列制备了多样化的目标化合物，包括通过铜介导的氧化环化组装呋喃[3,2-b]吡啶骨架。含有3,5-二取代的呋喃[3,2-b]吡啶的亚系列的优化提供了有效的，细胞活性的和高度选择性的CLKs抑制剂。对3,5,7-三取代的呋喃并[3,2-b]吡啶的激酶无活性子集的分析揭示了Hedgehog途径的亚微摩尔调节剂。

更新日期：2018-12-20

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