959617-89-1Relevant articles and documents
JNJ-67569762, A 2-Aminotetrahydropyridine-Based Selective BACE1 Inhibitor Targeting the S3 Pocket: From Discovery to Clinical Candidate
Rombouts, Frederik J. R.,Kusakabe, Ken-Ichi,Alexander, Richard,Austin, Nigel,Borghys, Herman,De Cleyn, Michel,Dhuyvetter, Deborah,Gijsen, Harrie J. M.,Hrupka, Brian,Jacobs, Tom,Jerhaoui, Soufyan,Lammens, Lieve,Leclercq, Laurent,Tsubone, Koichi,Ueno, Tatsuhiko,Morimoto, Kenji,Einaru, Shunsuke,Sumiyoshi, Hirokazu,Van Den Bergh, An,Vos, Ann,Surkyn, Michel,Teisman, Ard,Moechars, Diederik
, p. 14175 - 14191 (2021/10/12)
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.
