molecules of the year

January’s molecule, a Novartis FXR partial agonist (LMB763 (nidufexor)), modulates the farnesoid X nuclear receptor (FXR), a hot target for NASH due to promising prior clinical activity with bile acid-derived FXR agonists such as OCA. OCA, however, showed significant rates of side effects including itching (likely due to GPBAR1 bile acid receptor agonism) and elevated LDL cholesterol levels, which is problematic for the more heart-disease-susceptible NASH patient population. To complement their clinical, non-bile acid FXR full agonist, tripofexor, which addressed GPBAR1 selectivity, the Novartis team wanted a chemically distinct partial agonist candidate in case the elevated LDL levels turned out to be an on-target effect of FXR modulation. A high quality partial agonist starting point was identified from two parallel…