Discovery and Optimization of the First Highly Effective and Orally Available Galectin‑3 Inhibitors for Treatment of Fibrotic Disease

Galectin-3 is a carbohydrate-binding protein central
to regulating
mechanisms of diseases such as fibrosis, cancer, metabolic, inflammatory,
and heart disease. We recently found a high affinity (nM) thiodigalactoside
GB0139 which currently is in clinical development (PhIIb) as an inhaled
treatment of idiopathic pulmonary fibrosis. To enable treatment of
systemically galectin-3 driven disease, we here present the first
series of selective galectin-3 inhibitors combining high affinity
(nM) with oral bioavailability. This was achieved by optimizing galectin-3
specificity and physical chemical parameters for a series of disubstituted
monogalactosides. Further characterization showed that this class
of compounds reduced profibrotic gene expression in liver myofibroblasts
and displayed antifibrotic activity in CCl4-induced liver
fibrosis and bleomycin-induced lung fibrosis mouse models. On the
basis of the overall pharmacokinetic, pharmacodynamic, and safety
profile, GB1211 was selected as the clinical candidate and is currently
in phase IIa clinical trials as a potential therapy for liver cirrhosis
and cancer.