JNJ-67569762, A 2‑Aminotetrahydropyridine-Based Selective BACE1 Inhibitor Targeting the S3 Pocket: From Discovery to Clinical Candidate

The discovery of a novel 2-aminotetrahydropyridine
class of BACE1
inhibitors is described. Their pKa and lipophilicity were
modulated by a pending sulfonyl group, while good permeability and
brain penetration were achieved via intramolecular hydrogen bonding.
BACE1 selectivity over BACE2 was achieved in the S3 pocket by a novel
bicyclic ring system. An optimization addressing reactive metabolite
formation, cardiovascular safety, and CNS toxicity is described, leading
to the clinical candidate JNJ-67569762 (12), which gave
robust dose-dependent BACE1-mediated amyloid β lowering without
showing BACE2-dependent hair depigmentation in preclinical models.
We show that 12 has a favorable projected human dose
and PK and hence presented us with an opportunity to test a highly
selective BACE1 inhibitor in humans. However, 12 was
found to have a QT effect upon repeat dosing in dogs and its development
was halted in favor of other selective leads, which will be reported
in the future.