molecules of the month

The Janssen BACE1-selective inhibitor, JNJ-67569762, was a preclinical candidate for Alzheimer’s disease. Obtaining BACE1 over BACE2 selectivity was a major challenge in the field, and the molecule is 74x selective thanks to a bicyclic ring system in the S3 pocket. In in vivo models, BACE1-mediated PD was observed without BACE2-dependent hair depigmentation. The authors chose to work on a 2-amino-tetrahydropyridine scaffold, avoiding the 1,3-thiazine group linked to liver toxicity in clinical trials, and leveraged a sulfonyl group to lower pKa and increase lipophilicity. Unfortunately, in a 14-day dog study, a prolonged QTc signal was observed, despite a large in vitro window against hERG (patch clamp IC50 = 8.3 uM). Potential effects on hERG trafficking were postulated but not investigated further. The…