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<p>Several glucagon-like peptide-1 receptor (GLP-1R) agonists have been recognized as effective therapeutic strategies for T2DM and obesity. Our efforts focused on modifying the pyridine fragment and the region near the benzo[<i>d</i>]imidazole moiety of <b>danuglipron</b> to reduce the inhibitory activity on the hERG channel while preserving its ability to activate GLP-1R, leading to the synthesis of 21 novel derivatives. An optimized indolecarboxylic acid derivative, <b>YK-11</b> (EC<sub>50</sub> = 7.5&#xa0;nM), showed promising ability in activating GLP-1R, with acceptable inhibition of the hERG ion channel (IC<sub>50</sub> = 34.3&#xa0;μM). Furthermore, the docking analysis of <b>YK-11</b> revealed that indolecarboxylic acid derivatives extended into the binding pocket of the GLP-1R protein in a similar manner to <b>danuglipron</b>, and the carboxyl group, methyl ester moiety, cyano group and cyclobutyl ether moiety of <b>YKF-11</b> created four hydrogen bonds with Lys197, Gln221 and Arg299, respectively. This study provided alternative approach for the future development of GLP-1R agonists.</p> Graphical Abstract <p></p>

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Discovery and optimization of novel indolecarboxylic acid derivative as potent glucagon-like peptide‑1 receptor agonists

  • 期刊论文

  • 发表日期：

    2025年5月14日

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  • Wanting Zhao,
  • Yuqian Yin,
  • Zhuo Shi,
  • Ke Yang,
  • Xinglin Li,
  • Yushe Yang,
  • Tongfei Jing,
  • Zhenghui Kang

摘要

Several glucagon-like peptide-1 receptor (GLP-1R) agonists have been recognized as effective therapeutic strategies for T2DM and obesity. Our efforts focused on modifying the pyridine fragment and the region near the benzo[d]imidazole moiety of danuglipron to reduce the inhibitory activity on the hERG channel while preserving its ability to activate GLP-1R, leading to the synthesis of 21 novel derivatives. An optimized indolecarboxylic acid derivative, YK-11 (EC50 = 7.5 nM), showed promising ability in activating GLP-1R, with acceptable inhibition of the hERG ion channel (IC50 = 34.3 μM). Furthermore, the docking analysis of YK-11 revealed that indolecarboxylic acid derivatives extended into the binding pocket of the GLP-1R protein in a similar manner to danuglipron, and the carboxyl group, methyl ester moiety, cyano group and cyclobutyl ether moiety of YKF-11 created four hydrogen bonds with Lys197, Gln221 and Arg299, respectively. This study provided alternative approach for the future development of GLP-1R agonists.

Graphical Abstract