ArticleJournal of medicinal chemistry2015
Utilizing structures of CYP2D6 and BACE1 complexes to reduce risk of drug-drug interactions with a novel series of centrally efficacious BACE1 inhibitors.
Article in Journal of medicinal chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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The trial behind it
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Who cites it
20 citing papers in PubMed, 78 citations in OpenAlex.
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- Unveiling the antitumor potential of novel N-(substituted-phenyl)-8-methoxycoumarin-3-carboxamides as dual inhibitors of VEGFR2 kinase and cytochrome P450 for targeted treatment of hepatocellular carcinoma.Frontiers in chemistry · 2023Article
- A Review of the Recent Advances in Alzheimer's Disease Research and the Utilization of Network Biology Approaches for Prioritizing Diagnostics and Therapeutics.Diagnostics (Basel, Switzerland) · 2022Review
- Resveratrol and neuroprotection: an insight into prospective therapeutic approaches against Alzheimer's disease from bench to bedside.Molecular neurobiology · 2022Review
- Roles of cytochrome P450 enzymes in pharmacology and toxicology: Past, present, and future.Advances in pharmacology (San Diego, Calif.) · 2022Article
- Occurrence of Morpholine in Central Nervous System Drug Discovery.ACS chemical neuroscience · 2021Article
- Sulfur-containing therapeutics in the treatment of Alzheimer's disease.Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents · 2021Article
- In vitro and in silico studies of interaction of synthetic 2,6,9-trisubstituted purine kinase inhibitors BPA-302, BP-21 and BP-117 with liver drug-metabolizing cytochromes P450Physiological research · 2020Article
- Biotransformation, Using Recombinant CYP450-Expressing Baker's Yeast Cells, Identifies a Novel CYP2D6.10ACS omega · 2018Article
- Highlights in BACE1 Inhibitors for Alzheimer's Disease Treatment.Frontiers in chemistry · 2018Review
- A combinatorial approach for the discovery of cytochrome P450 2D6 inhibitors from nature.Scientific reports · 2017Article
- Conformational dynamics of cathepsin D and binding to a small-molecule BACE1 inhibitor.Journal of computational chemistry · 2017Article
- Aminomethyl-Derived Beta Secretase (BACE1) Inhibitors: Engaging Gly230 without an Anilide Functionality.Journal of medicinal chemistry · 2017Article
- Chemoproteomic profiling reveals that cathepsin D off-target activity drives ocular toxicity of β-secretase inhibitors.Nature communications · 2016Article
- Seizure protein 6 and its homolog seizure 6-like protein are physiological substrates of BACE1 in neurons.Molecular neurodegeneration · 2016Article
- Recent Structural Insights into Cytochrome P450 Function.Trends in pharmacological sciences · 2016Review
- Constant pH Molecular Dynamics Reveals pH-Modulated Binding of Two Small-Molecule BACE1 Inhibitors.The journal of physical chemistry letters · 2016Article
- How does curcumin work with poor bioavailability? Clues from experimental and theoretical studies.Scientific reports · 2016Article
- Combined experimental and theoretical studies of regio- and stereoselectivity in reactions of β-isoxazolyl- and β-imidazolyl enamines with nitrile oxides.Beilstein journal of organic chemistry · 2016Article
Corrections and comments
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Authors and funding
31 authors at 3 institutions in 2 countries.
Funding
Abstract
In recent years, the first generation of β-secretase (BACE1) inhibitors advanced into clinical development for the treatment of Alzheimer's disease (AD). However, the alignment of drug-like properties and selectivity remains a major challenge. Herein, we describe the discovery of a novel class of potent, low clearance, CNS penetrant BACE1 inhibitors represented by thioamidine 5. Further profiling suggested that a high fraction of the metabolism (>95%) was due to CYP2D6, increasing the potential risk for victim-based drug-drug interactions (DDI) and variable exposure in the clinic due to the polymorphic nature of this enzyme. To guide future design, we solved crystal structures of CYP2D6 complexes with substrate 5 and its corresponding metabolic product pyrazole 6, which provided insight into the binding mode and movements between substrate/inhibitor complexes. Guided by the BACE1 and CYP2D6 crystal structures, we designed and synthesized analogues with reduced risk for DDI, central efficacy, and improved hERG therapeutic margins.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.