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
  • 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.
PMID: 34553934 DOI: 10.1021/acs.jmedchem.1c00935
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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