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

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

  • J Med Chem. 2021 Oct 14;64(19):14175-14191. doi: 10.1021/acs.jmedchem.1c00935.
Frederik J R Rombouts 1 Ken-Ichi Kusakabe 2 Richard Alexander 3 Nigel Austin 1 Herman Borghys 1 Michel De Cleyn 1 Deborah Dhuyvetter 1 Harrie J M Gijsen 1 Brian Hrupka 1 Tom Jacobs 1 Soufyan Jerhaoui 1 Lieve Lammens 1 Laurent Leclercq 1 Koichi Tsubone 2 Tatsuhiko Ueno 2 Kenji Morimoto 2 Shunsuke Einaru 2 Hirokazu Sumiyoshi 2 An Van den Bergh 1 Ann Vos 1 Michel Surkyn 1 Ard Teisman 1 Diederik Moechars 1
Affiliations

Affiliations

  • 1 Janssen Research & Development, Janssen Pharmaceutica N. V., Turnhoutseweg 30, Beerse B-2340, Belgium.
  • 2 Shionogi Pharmaceutical Research Center, Ltd., 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
  • 3 Janssen Research & Development, Welsh & McKean Roads, Spring House, Pennsylvania 19477, United States.
Abstract

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.

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