2. Academic Validation
  3. 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

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

Affiliations

  • 1 Research & Early Development, Bristol Myers Squibb Company, P.O. Box 4000, Princeton, NJ 08543, United States. Electronic address: chunjian.liu@bms.com.
  • 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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