Discovery of Atabecestat (JNJ-54861911): A Thiazine-Based β-Amyloid Precursor Protein Cleaving Enzyme 1 Inhibitor Advanced to the Phase 2b/3 EARLY Clinical Trial
| Autor: | Shiho Yamamoto, Hisanori Ito, Takushi Kanazu, Shunsuke Einaru, Shuji Yonezawa, Norihiko Tanimoto, Takahiko Yamamoto, Luc Tritsmans, Takuya Oguma, Akira Kato, Gaku Sakaguchi, Ken-ichi Kusakabe, Katsunori Sakai, Tatsuhiko Ueno, Akihiro Matsuda, Akihiro Hori, Kenji Morimoto, Yoshitaka Yamaguchi, Yoshiyasu Baba, Maarten Timmers, Naoya Asada, Koriyama Yuji |
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| Rok vydání: | 2021 |
| Předmět: |
Male
ERG1 Potassium Channel Pyridines medicine.medical_treatment Irreversible binding Thiazines Covalent binding Pharmacology 01 natural sciences Rats Sprague-Dawley Mice 03 medical and health sciences chemistry.chemical_compound Dogs Alzheimer Disease β amyloid Thiazine Drug Discovery medicine Amyloid precursor protein Animals Aspartic Acid Endopeptidases Humans Protease Inhibitors 030304 developmental biology chemistry.chemical_classification 0303 health sciences Amyloid beta-Peptides Protease biology Chemistry 0104 chemical sciences Clinical trial 010404 medicinal & biomolecular chemistry Enzyme Early Termination of Clinical Trials biology.protein Molecular Medicine Female Amyloid Precursor Protein Secretases |
| Zdroj: | Journal of Medicinal Chemistry. 64:1873-1888 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | Accumulation of amyloid β peptides (Aβ) is thought to be one of the causal factors of Alzheimer's disease (AD). The aspartyl protease β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the rate-limiting protease for Aβ production, and therefore, BACE1 inhibition is a promising therapeutic approach for the treatment of AD. Starting with a dihydro-1,3-thiazine-based lead, Compound J, we discovered atabecestat 1 (JNJ-54861911) as a centrally efficacious BACE1 inhibitor that was advanced into the EARLY Phase 2b/3 clinical trial for the treatment of preclinical AD patients. Compound 1 demonstrated robust and dose-dependent Aβ reduction and showed sufficient safety margins in preclinical models. The potential of reactive metabolite formation was evaluated in a covalent binding study to assess its irreversible binding to human hepatocytes. Unfortunately, the EARLY trial was discontinued due to significant elevation of liver enzymes, and subsequent analysis of the clinical outcomes showed dose-related cognitive worsening. |
| Databáze: | OpenAIRE |
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