The β-amyloid precursor protein-cleaving enzyme 1 (BACE1) inhibitor JNJ-54861911, a candidate for the treatment of Alzheimer's disease, was withdrawn from clinical trials due to drug-induced liver inj Show more
The β-amyloid precursor protein-cleaving enzyme 1 (BACE1) inhibitor JNJ-54861911, a candidate for the treatment of Alzheimer's disease, was withdrawn from clinical trials due to drug-induced liver injury (DILI). This paper describes our investigation of the metabolism of JNJ-54861911 to understand the potential contribution to the observed DILI. In human hepatocytes, JNJ-54861911 is metabolized by CYP450 3A4 to a reactive intermediate (RI), which undergoes glutathione (GSH) addition at C6 of the 2-amino-4-methyl-1,3-thiazin-4-yl moiety via glutathione S-transferase α1 (GSTA1) catalysis. Despite the preponderant role of CYP3A4 as an enabler, the adduct has the same level of oxidation as that of JNJ-54861911. The exact mechanism of RI formation might involve a sulfoxide (with further reduction) or tautomeric forms of JNJ-54861911 bearing a reactive thiazinium cation activating both the C2 and C6 positions. The cell pellet from the human hepatocyte incubated with Show less