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
- 15 February 2021
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 64 (4), 1873-1888
- https://doi.org/10.1021/acs.jmedchem.0c01917
Abstract
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.Keywords
This publication has 50 references indexed in Scilit:
- Clinical and Biomarker Changes in Dominantly Inherited Alzheimer's DiseaseThe New England Journal of Medicine, 2012
- Robust Central Reduction of Amyloid-β in Humans with an Orally Available, Non-Peptidic β-Secretase InhibitorJournal of Neuroscience, 2011
- Bace2 Is a β Cell-Enriched Protease that Regulates Pancreatic β Cell Function and MassCell Metabolism, 2011
- Structural Alert/Reactive Metabolite Concept as Applied in Medicinal Chemistry to Mitigate the Risk of Idiosyncratic Drug Toxicity: A Perspective Based on the Critical Examination of Trends in the Top 200 Drugs Marketed in the United StatesChemical Research in Toxicology, 2011
- Synthesis and Applications of tert-ButanesulfinamideChemical Reviews, 2010
- Medicinal Chemistry of hERG Optimizations: Highlights and Hang-UpsJournal of Medicinal Chemistry, 2006
- THE IMPACT OF P-GLYCOPROTEIN ON THE DISPOSITION OF DRUGS TARGETED FOR INDICATIONS OF THE CENTRAL NERVOUS SYSTEM: EVALUATION USING THE MDR1A/1B KNOCKOUT MOUSE MODELDrug Metabolism and Disposition, 2004
- Classification Analysis of P-Glycoprotein Substrate SpecificityJournal of Drug Targeting, 2003
- α‐Chloro Enamines, Reactive Intermediates for Synthesis: 1‐Chloro‐ N,N ,2‐TrimethylpropenylaminePublished by Wiley ,2003
- Hepatotoxicity with ThiazolidinedionesDrug Safety, 2001