JNJ-67569762, A 2-Aminotetrahydropyridine-Based Selective BACE1 Inhibitor Targeting the S3 Pocket: From Discovery to Clinical Candidate
| Autor: | Ann Vos, Lieve Lammens, Richard Alexander, Frederik J. R. Rombouts, Michel Surkyn, Kenji Morimoto, Laurent Leclercq, Nigel Austin, Koichi Tsubone, Tatsuhiko Ueno, Michel Anna Jozef De Cleyn, Deborah Dhuyvetter, Ken-ichi Kusakabe, Ard Teisman, Diederik Moechars, Tom Jacobs, An Van Den Bergh, Hirokazu Sumiyoshi, Herman Borghys, Shunsuke Einaru, Soufyan Jerhaoui, Brian Joel Hrupka, Harrie J.M. Gijsen |
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| Rok vydání: | 2021 |
| Předmět: |
Models
Molecular Sulfonyl chemistry.chemical_classification Pyrrolidines Cardiovascular safety Dose-Response Relationship Drug Molecular Structure Bicyclic molecule Amyloid β Chemistry Pharmacology Crystallography X-Ray Highly selective Cns toxicity Structure-Activity Relationship mental disorders Drug Discovery Reactive metabolite Lipophilicity Aspartic Acid Endopeptidases Humans Molecular Medicine Amyloid Precursor Protein Secretases |
| Zdroj: | Journal of Medicinal Chemistry. 64:14175-14191 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.1c00935 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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