ArticleChemMedChem2015
Freezing the Bioactive Conformation to Boost Potency: The Identification of BAY 85-8501, a Selective and Potent Inhibitor of Human Neutrophil Elastase for Pulmonary Diseases.
Article in ChemMedChem, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers, 1 of them a synthesis that pooled it.
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Who cites it
32 citing papers in PubMed, 1 synthesis or guideline pooled it, 66 citations in OpenAlex.
- Neutrophil elastase in bronchiectasis.Respiratory research · 2017Pooled it
- Human Neutrophil Elastase and the Protein-Storm Axis: Reversible Synthetic Inhibitors in Inflammatory Disease.Molecules (Basel, Switzerland) · 2026Review
- Core Flipping in Lead Optimization: Rank Ordering Using λ-Dynamics.Journal of chemical information and modeling · 2025Article
- Synergistic and Antagonistic Mechanisms ofMolecules (Basel, Switzerland) · 2025Article
- Investigating Polypharmacology through Targeting Known Human Neutrophil Elastase Inhibitors to Proteinase 3.Journal of chemical information and modeling · 2024Article
- Expression and purification of human neutrophil proteinase 3 from insect cells and characterization of ligand binding.PloS one · 2024Article
- Target 2035 - an update on private sector contributions.RSC medicinal chemistry · 2023Article
- The roles of neutrophils in non-tuberculous mycobacterial pulmonary disease.Annals of clinical microbiology and antimicrobials · 2023Review
- Neutrophils as emerging protagonists and targets in chronic inflammatory diseases.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2022Review
- Human Antibody Domains and Fragments Targeting Neutrophil Elastase as Candidate Therapeutics for Cancer and Inflammation-Related Diseases.International journal of molecular sciences · 2021Article
- Discrimination of Methionine Sulfoxide and Sulfone by Human Neutrophil Elastase.Molecules (Basel, Switzerland) · 2021Article
- Electrophilic reactivities of cyclic enones and α,β-unsaturated lactones.Chemical science · 2021Article
- Protease-Specific Biomarkers to Analyse Protease Inhibitors for Emphysema Associated with Alpha 1-Antitrypsin Deficiency. An Overview of Current Approaches.International journal of molecular sciences · 2021Review
- Exploration of nitrogen heterocycle scaffolds for the development of potent human neutrophil elastase inhibitors.Bioorganic & medicinal chemistry · 2021Article
- Synthesis and evaluation of benzenesulfonic acid derivatives as human neutrophil elastase (hNE) inhibitors.Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents · 2021Article
- Hindrance of the Proteolytic Activity of Neutrophil-Derived Serine Proteases by Serine Protease Inhibitors as a Management of Cardiovascular Diseases and Chronic Inflammation.Frontiers in chemistry · 2021Review
- Targeting Neutrophils to Treat Acute Respiratory Distress Syndrome in Coronavirus Disease.Frontiers in pharmacology · 2020Review
- Characterization of ecotin homologs from Campylobacter rectus and Campylobacter showae.PloS one · 2020Article
- Neutrophilia and NETopathy as Key Pathologic Drivers of Progressive Lung Impairment in Patients With COVID-19.Frontiers in pharmacology · 2020Article
- Neutrophil Elastase and Neutrophil Extracellular Traps in the Tumor Microenvironment.Advances in experimental medicine and biology · 2020Review
Corrections and comments
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Authors and funding
22 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Human neutrophil elastase (HNE) is a key protease for matrix degradation. High HNE activity is observed in inflammatory diseases. Accordingly, HNE is a potential target for the treatment of pulmonary diseases such as chronic obstructive pulmonary disease (COPD), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), bronchiectasis (BE), and pulmonary hypertension (PH). HNE inhibitors should reestablish the protease-anti-protease balance. By means of medicinal chemistry a novel dihydropyrimidinone lead-structure class was identified. Further chemical optimization yielded orally active compounds with favorable pharmacokinetics such as the chemical probe BAY-678. While maintaining outstanding target selectivity, picomolar potency was achieved by locking the bioactive conformation of these inhibitors with a strategically positioned methyl sulfone substituent. An induced-fit binding mode allowed tight interactions with the S2 and S1 pockets of HNE. BAY 85-8501 ((4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile) was shown to be efficacious in a rodent animal model related to ALI. BAY 85-8501 is currently being tested in clinical studies for the treatment of pulmonary diseases.
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