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

Abstract

Galectin-3 (Gal-3) is a galactose-binding lectin involved in pathologies such as inflammation, fibrosis, heart disease, and tumor progression. Here, we report N-aryl-N-(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 11, binds to Gal-3 with excellent affinity (K(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 (CC(50) > 300 μM). Compound 11 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 ACTA2, COL1A2, and FN1. These findings implicate compound 11 as a promising candidate for further preclinical development in the context of fibrotic disease.