Galectin-3 is a β-D-galactopyranoside specific lectin which is involved in the pathology of fibrosis and cancer. We recently finalized a successful phase I/IIa study with our galectin-3 inhibitor, TD139, which is being developed as an inhaled treatment of Idiopatic pulmonary fibrosis (IPF). Since genetic depletion or inhibition of galectin-3 reduces fibrosis in other organs such as liver, kidney and heart, there is a need for a systemically available galectin-3 inhibitor. We report here how we developed the first orally available high affinity (nM) galectin-3 inhibitors and the effects of these in PD models of fibrosis and cancer.<br/><br/>Designing small high affinity lectin inhibitors with a natural saccharide as a starting point is a major challenge. In general mono- and disaccharides bind with an affinity in the low µM-mM range due to that the lectin binding sites are shallow and polar. Inhibitors with high polarity also in general have limited oral bioavailability, which indeed is the case for the disaccharide TD139. By introduction of non-natural aromatic substituents to the 1 and 3-position of α-D-galactopyranoside the polar surface area was reduced and lipophilicity increased to result in compounds with PK properties suitable for oral administration. Then high affinity compounds could be achieved by the use of specific interactions, such as fluorine-amide, phenyl-arginine, sulfur- π and halogen bonds.<br/><br/>Further, we have shown that these compounds reduce development of fibrosis in a CCl4 mouse model and that they also reduce tumor growth and metastasis in a model of Lewis Lung Carcinoma. We are currently in the process of taking candidates of this class to man for development of new treatments of fibrosis (NASH) and cancer.

First class of orally available mono-saccharide galectin-3 inhibitors for treatment of fibrosis (NASH) and cancer

256th National Meeting (2018)

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