posted on 2021-05-14, 13:34authored byLi Xu, Richard A. Hartz, Brett R. Beno, Kaushik Ghosh, Jinal K. Shukla, Amit Kumar, Dipal Patel, Narasimharaju Kalidindi, Nadine Lemos, Shashyendra Singh Gautam, Anoop Kumar, Bruce A. Ellsworth, Devang Shah, Harinath Sale, Dong Cheng, Alicia Regueiro-Ren
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.