BMS-932481

BMS-932481 is an orally active, non-NSAID bicyclic pyrimidine small molecule that acts as a **γ-secretase modulator (GSM)**. Developed by Bristol Myers Squibb for the potential treatment of Alzheimer's disease, it selectively shifts the cleavage of amyloid precursor protein (APP) by the γ-secretase enzyme. Specifically, it reduces the production of longer, more amyloidogenic peptides like Aβ40 and Aβ42 while increasing the production of shorter, less toxic peptides such as Aβ37 and Aβ38. Unlike γ-secretase inhibitors (GSIs), GSMs do not block the processing of other critical substrates like Notch, potentially avoiding side effects associated with Notch inhibition. Clinical development was halted after a multiple ascending dose study in healthy volunteers revealed significant drug-induced liver injury (DILI), characterized by dose-dependent hepatocellular damage.