Identification of benzothiazole derived monosaccharides as potent, selective, and orally bioavailable inhibitors of human and mouse galectin-3; a rare example of using a S···O binding interaction for drug design

  • Bioorg Med Chem. 2024 Mar 1:101:117638. doi: 10.1016/j.bmc.2024.117638.
Chunjian Liu  1 ,  Wei Wang  2 ,  Jianxin Feng  2 ,  Brett Beno  2 ,  Thiruvenkadam Raja  3 ,  Jacob Swidorski  2 ,  Raju K V L P Manepalli  3 ,  Muthalagu Vetrichelvan  3 ,  Prasada Rao Jalagam  3 ,  Satheesh K Nair  3 ,  Anuradha Gupta  3 ,  Manoranjan Panda  3 ,  Kaushik Ghosh  3 ,  Jinal Kaushikkumar Shukla  3 ,  Harinath Sale  3 ,  Devang Shah  3 ,  Shashyendra Singh Gautam  3 ,  Dipal Patel  2 ,  Arvind Mathur  2 ,  Bruce A Ellsworth  2 ,  Dong Cheng  2 ,  Alicia Regueiro-Ren  2
Affiliations
  • 1. Research & Early Development, Bristol Myers Squibb Company, P.O. Box 4000, Princeton, NJ 08543, United States. Electronic address: [email protected].
  • 2. Research & Early Development, Bristol Myers Squibb Company, P.O. Box 4000, Princeton, NJ 08543, United States.
  • 3. Biocon-Bristol Myers Squibb Research and Development Center, Bangalore 560099, India.
PMID: 38394996 DOI: 10.1016/j.bmc.2024.117638
Abstract

As a result of our continued efforts to pursue Gal-3 inhibitors that could be used to fully evaluate the potential of Gal-3 as a therapeutic target, two novel series of benzothiazole derived Monosaccharides as potent (against both human and mouse Gal-3) and orally bioavailable Gal-3 inhibitors, represented by 4 and 5, respectively, were identified. These discoveries were made based on proposals that the benzothiazole sulfur atom could interact with the carbonyl oxygen of G182/G196 in h/mGal-3, and that the anomeric triazole moiety could be modified into an N-methyl carboxamide functionality. The interaction between the benzothiazole sulfur and the carbonyl oxygen of G196 in mGal-3 was confirmed by an X-ray co-crystal structure of early lead 9, providing a rare example of using a S···O binding interaction for drug design. It was found that for both the series, methylation of 3-OH in the Monosaccharides caused no loss in h & mGal-3 potencies but significantly improved permeability of the molecules.

Keywords
Benzothiazole; Galectin-3 (Gal-3); Galectin-3 (Gal-3) inhibitor; Interaction between sulfur and carbonyl oxygen atoms; Monosaccharide galectin-3 (Gal-3) inhibitor; X-ray co-crystal structure with Galectin-3 (Gal-3).
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