Discovery of Galactopyranose‐1‐Carboxamides as a New Class of Small, Novel, Potent, Selective, and Orally Active Galectin‐3 Inhibitors

Galectin‐3 (Gal‐3), a β‐galactoside‐binding lectin, is implicated in diverse cellular functions ranging from immune response modulation to tissue homeostasis. Notably, increased Gal‐3 expression has been linked to the progression of numerous diseases, including cancer, fibrosis, and cardiovascular disorders, underscoring its potential as a therapeutic target. Small molecule inhibitors have been discovered and are valuable tools to study such diseases. We report here the discovery of novel, galactose‐based, small molecule inhibitors such as compound 12 which are orally bioavailable and show efficacy in a mouse model of acute liver injury and fibrosis (CCl4 model). The use of structure‐based drug design (docking of a virtual library of amides based on acid 2) was key in the process towards potent, nanomolar inhibitors.