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

  • ChemMedChem. 2025 Mar 12:e202401012. doi: 10.1002/cmdc.202401012.
Cornelia Zumbrunn  1 ,  Luboš Remen  1 ,  Christoph P Sager  1 ,  Corinna Grisostomi  1 ,  Christina Stamm  1 ,  Daniela Krüsi  1 ,  Sven Glutz  1 ,  Gunther Schmidt  1 ,  Oliver Nayler  1 ,  Marc Iglarz  1 ,  Aengus Mac Sweeney  1 ,  Alain Chambovey  1 ,  Manon Müller  1 ,  Celia Mueller  1 ,  Geoffroy Bourquin  1 ,  Solange Meyer  1 ,  Eva Hühn  1 ,  Christophe Cattaneo  1 ,  Magali Vercauteren  1 ,  John Gatfield  1 ,  Martin H Bolli  1
Affiliations
  • 1. Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, CH-4123, Allschwil, Switzerland.
Abstract

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.

Keywords
Galectin-3; cancer; fibrosis; inflammation; inhibitor.
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