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

Authors

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

Published in

Molecular diversity. May 14, 2025. Epub May 14, 2025.

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.

PMID:
40366550
Bibliographic data and abstract were imported from PubMed on 14 May 2025.

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