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