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

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

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.

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