Design, Synthesis, and Biological Evaluation of Pentacyclic Triterpene Derivatives as Intestinal FXR Antagonists for Type 2 Diabetes

Abstract Intestinal farnesoid X receptor (FXR) antagonism has emerged as a strategy to enhance endogenous glucagon-like peptide-1 (GLP-1) secretion and improve metabolic control in type 2 diabetes mellitus (T2DM). Dihydrooleanolic acid methyl ester (DKS26) served as the scaffold for the synthesis of 64 pentacyclic triterpene derivatives modified at the terminal carboxyl group and C-3/C-12 positions. Esterification of the terminal carboxylate emerged as a determinant of FXR antagonism, identifying 4l bearing a tetrazole-containing side chain and C-12 hydroxyl motif. Compound 4l antagonized FXR in a TR-FRET assay (IC50 = 11.79 μM), a fivefold improvement over DKS26. In NCI-H716 cells, 4l reduced NR0B2 (SHP) mRNA expression and markedly stimulated GLP-1 secretion. In HFD/STZ-induced diabetic mice, oral 4l improved glycemia, increased circulating GLP-1 and insulin, and alleviated dyslipidemia and organ injury markers. These findings establish the pentacyclic triterpene scaffold as a platform for FXR antagonism and identify 4l as a lead for further optimization.