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

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 (EC = 7.5 nM), showed promising ability in activating GLP-1R, with acceptable inhibition of the hERG ion channel (IC = 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.