Synthesis, Structure-Activity Relationships, and In Vivo Evaluation of Novel Tetrahydropyran-Based Thiodisaccharide Mimics as Galectin-3 Inhibitors

  • J Med Chem. 2021 May 27;64(10):6634-6655. doi: 10.1021/acs.jmedchem.0c02001.
Li Xu  1 ,  Richard A Hartz  1 ,  Brett R Beno  2 ,  Kaushik Ghosh  3 ,  Jinal K Shukla  3 ,  Amit Kumar  3 ,  Dipal Patel  4 ,  Narasimharaju Kalidindi  3 ,  Nadine Lemos  3 ,  Shashyendra Singh Gautam  3 ,  Anoop Kumar  3 ,  Bruce A Ellsworth  1 ,  Devang Shah  3 ,  Harinath Sale  3 ,  Dong Cheng  5 ,  Alicia Regueiro-Ren  1
Affiliations
  • 1. Department of Small Molecule Drug Discovery, Bristol Myers Squibb Company, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543, United States.
  • 2. Department of Computer-Aided Drug Design & Molecular Analytics, Bristol Myers Squibb Company, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543, United States.
  • 3. Biocon-Bristol Myers Squibb Research and Development Center, Biocon Park, Plot No. 2 & 3, Bommasandra Phase IV, Jigani Link Road, Bangalore 560099, India.
  • 4. Department of Metabolism and Pharmacokinetics, Bristol Myers Squibb Company, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543, United States.
  • 5. Department of Cardiovascular and Fibrosis Discovery Biology, Bristol Myers Squibb Company, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543, United States.
PMID: 33988358 DOI: 10.1021/acs.jmedchem.0c02001
Abstract

Galectin-3 is a member of a family of β-galactoside-binding proteins. A substantial body of literature reports that Galectin-3 plays important roles in Cancer, inflammation, and fibrosis. Small-molecule Galectin-3 inhibitors, which are generally lactose or galactose-based derivatives, have the potential to be valuable disease-modifying agents. In our efforts to identify novel Galectin-3 disaccharide mimics to improve drug-like properties, we found that one of the monosaccharide subunits can be replaced with a suitably functionalized tetrahydropyran ring. Optimization of the structure-activity relationships around the tetrahydropyran-based scaffold led to the discovery of potent Galectin-3 inhibitors. Compounds 36, 40, and 45 were selected for further in vivo evaluation. The synthesis, structure-activity relationships, and in vivo evaluation of novel tetrahydropyran-based Galectin-3 inhibitors are described.