<i>N</i> -Aryl- <i>N</i> -Lactosylamides as Potent and Highly Selective Inhibitors of Galectin-3 with Antifibrotic Activity

Galectin-3 (Gal-3) is a galactose-binding lectin involved in pathologies such as inflammation, fibrosis, heart disease, and tumor progression. Here, we report <i>N</i>-aryl-<i>N</i>-(thio)lactosylamides as a novel class of Gal-3 inhibitors. A structure-activity study identified 6-carboxyindol-4-yl amide as a key pharmacophoric motif within this series. The most potent inhibitor based on this motif, compound <b>11</b>, binds to Gal-3 with excellent affinity (<i>K</i>_d = 5.7 nM) and selectivity (390-fold over Gal-1). Further in vitro characterization of this compound demonstrated high metabolic stability and no cytotoxicity (CC₅₀ > 300 μM). Compound <b>11</b> effectively engages Gal-3 with greater activity in macrophage-like than monocyte-like THP1 cells, without affecting inflammation via LPS-induced release of TNFα. In TGFβ-stimulated LX2 hepatic stellate cells, it downregulates profibrotic signaling as assessed by the reduced expression of <i>ACTA2</i>, <i>COL1A2</i>, and <i>FN1</i>. These findings implicate compound <b>11</b> as a promising candidate for further preclinical development in the context of fibrotic disease.