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

IF 3.9 2区化学 Q2 CHEMISTRY, APPLIED

Molecular Diversity Pub Date : 2025-05-14 DOI:10.1007/s11030-025-11213-7

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

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Abstract

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.

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新型吲哚羧酸衍生物作为胰高血糖素样肽- 1受体激动剂的发现和优化。

几种胰高血糖素样肽-1受体（GLP-1R）激动剂已被认为是治疗2型糖尿病和肥胖的有效策略。我们的工作重点是修饰丹格列酮的吡啶片段和苯并[d]咪唑部分附近的区域，以降低对hERG通道的抑制活性，同时保持其激活GLP-1R的能力，从而合成21种新的衍生物。优化后的吲哚羧酸衍生物YK-11 （EC50 = 7.5 nM）对GLP-1R具有良好的激活作用，对hERG离子通道具有良好的抑制作用（IC50 = 34.3 μM）。此外，对YK-11的对接分析发现，吲哚羧酸衍生物以与danuglipron相似的方式延伸到GLP-1R蛋白的结合口袋中，YK-11的羧基、甲酯部分、氰基和环丁基醚部分分别与Lys197、Gln221和Arg299形成4个氢键。本研究为GLP-1R激动剂的未来开发提供了另一种途径。

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来源期刊

Molecular Diversity 化学-化学综合

CiteScore

7.30

自引率

7.90%

发文量

219

审稿时长

2.7 months

期刊介绍： Molecular Diversity is a new publication forum for the rapid publication of refereed papers dedicated to describing the development, application and theory of molecular diversity and combinatorial chemistry in basic and applied research and drug discovery. The journal publishes both short and full papers, perspectives, news and reviews dealing with all aspects of the generation of molecular diversity, application of diversity for screening against alternative targets of all types (biological, biophysical, technological), analysis of results obtained and their application in various scientific disciplines/approaches including: combinatorial chemistry and parallel synthesis; small molecule libraries; microwave synthesis; flow synthesis; fluorous synthesis; diversity oriented synthesis (DOS); nanoreactors; click chemistry; multiplex technologies; fragment- and ligand-based design; structure/function/SAR; computational chemistry and molecular design; chemoinformatics; screening techniques and screening interfaces; analytical and purification methods; robotics, automation and miniaturization; targeted libraries; display libraries; peptides and peptoids; proteins; oligonucleotides; carbohydrates; natural diversity; new methods of library formulation and deconvolution; directed evolution, origin of life and recombination; search techniques, landscapes, random chemistry and more;