Development and Evaluation of Benzofuran Oxoacetic Acid Compounds as EPAC1 Activators

Exchange protein directly activated by cAMP 1 (EPAC1) modulates Rap signaling and fibrosis. We report benzofuran oxoacetic acids as non-nucleotide EPAC1 agonists. Convergent synthesis delivered C2-diversified analogues (overall yields ≈ 3-7%). Fluorescent competition at isolated CNBDs mapped isoform engagement: several analogues favored EPAC1 (e.g., <b>DM244</b>, <b>DM357</b>, and <b>DM408</b>), <b>DM312</b> favored EPAC2, and small C2 changes tuned bias. In cells, EPAC1-transfected U2OS assays showed significant Rap1-GTP increases for <b>DM243</b>, <b>DM244,</b> and <b>DM245</b>, with no activation in EPAC2 cells and no detectable protein kinase A activity. In disease-relevant contexts, the series attenuated IL-6/STAT3 signaling in human umbilical vascular endothelial cells and inhibited TGF-β1-induced fibroblast-to-myofibroblast transition (αSMA, Collagen I) with midmicromolar potencies; known drugs, <b>SB525334</b> and <b>nintedanib</b>, remained more potent, yet nintedanib was markedly more cytotoxic. Across assays, some binding-phenotype disconnects emerged, plausibly reflecting exposure, signaling bias, and cell-context effects. Overall, benzofuran oxoacetic acids provide EPAC-pathway probes with a favorable tolerability window and scope for potency optimization as antifibrotics.