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Go with the flow: de-orphaning focused combinatorial libraries

The fast pace of drug discovery programs, aided by high-throughput screening campaigns, often relies on the generation of combinatorial libraries to identify new chemical entities. The Ugi 4- and 3-component reactions in particular [1], have proven to be robust in producing both tool compounds and drugs [2, 3]. Here we report a high-throughput entry into the imidazopyridine scaffold, using a microfluidic-assisted synthesis setup, coupled to a target prediction tool to de-orphan a focused compound library with high success rate, and identify an innovative GPCR-inhibiting chemotype. Combinatorial compounds were correctly identified as ligand-efficient adenosine A1/2B, and adrenergic α1A/B inhibitors with K i values in the low micromolar range.

References

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    Ugi M: Angew Chem Int Ed. 1962, 1: 8-21. 10.1002/anie.196200081.

  2. 2.

    Beck M, Srivastava S, Khoury K, Herdtweck E, Dömling A: Mol Div. 2010, 14: 479-491. 10.1007/s11030-010-9249-2.

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    Kalinski C, Lemoine H, Schmidt J, Burdack C, Kolb J, Umkehrer M, Ross G: Synthesis. 2008, 24: 4007-4011.

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Author information

Correspondence to Michael Reutlinger.

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Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0), which permits use, duplication, adaptation, distribution, and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

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Keywords

  • Combinatorial Library
  • High Success Rate
  • Target Prediction
  • Fast Pace
  • Micromolar Range