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Cited by 65Protease and Inhibitor MechanismsEnzyme function and inhibitionComputational Drug Discovery Methods

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

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von Nussbaum, Franz, Li, Volkhart M.‐J., Allerheiligen, Swen, Anlauf, Sonja, Bärfacker, Lars, Bechem, Martin, Delbeck, Martina, Fitzgerald, Mary F. +14 more·2015·ChemMedChem
DOI 10.1002/cmdc.201500131PMC PMC4515084
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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 ((4 S)‐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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  • Inhibitor drugs targeting HNE are small non-proteinaceous synthetic molecules.

    “However, PK101 and the optimal HNE peptide substrates selected from the combinatorial library contain unnatural amino acid residues [20], and the inhibitor drugs targeting HNE are small non-proteinaceous synthetic molecules [22,23].”

    From Discrimination of Methionine Sulfoxide and Sulfone by Human Neutrophil Elastase (2021) · cites this paper as [23]

    The Introduction (Figure 2 caption) says that biologicals such as elafin were the first class of HNE-inhibiting drugs, and describes small-molecule drugs as another class. Thus the paper contradicts the unqualified claim that HNE inhibitor drugs are small non-proteinaceous synthetic molecules. (LLM, conf=0.88)

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  • Sulfone moieties are present in inhibitor drugs targeting HNE, including Sivelestat and BAY 85-8501.

    “This notion is consistent with the observation of sulfone moieties in inhibitor drugs targeting HNE, including Sivelestat [22] and the Bayer inhibitor, BAY 85-8501 [23].”

    From Discrimination of Methionine Sulfoxide and Sulfone by Human Neutrophil Elastase (2021) · cites this paper as [23]

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Authors
von Nussbaum, F., Li, V. M. ‐., Allerheiligen, S., Anlauf, S., Bärfacker, L., Bechem, M., Delbeck, M., Fitzgerald, M. F., Gerisch, M., Gielen‐Haertwig, H., Haning, H., Karthaus, D., Lang, D., Lustig, K., Meibom, D., Mittendorf, J., Rosentreter, U., Schäfer, M., Schäfer, S., Schamberger, J., Telan, L. A., & Tersteegen, A.
Affiliations
  • Bayer (Germany) (DE)
  • Bayer (United Kingdom) (GB)
Corresponding author
Li, Volkhart M.‐J.
ORCID
Venue
ChemMedChem
Publisher
Wiley
Published
2015-06-17
Volume
10
Issue
7
Pages
1163-1173
ISSN
  • 1860-7179 (ISSN-L)
  • 1860-7187
DOI
10.1002/cmdc.201500131
PMC
PMC4515084
OpenAlex
W1589151684
Cited by
65
References
0
Citations by year
2026: 3 · 2025: 3 · 2024: 3 · 2023: 7 · 2022: 3 · 2021: 8 · 2020: 10 · 2019: 6 · 2018: 5 · 2017: 9 · 2016: 5 · 2015: 3
FWCI
2.54
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • ChemMedChem (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Enzyme function and inhibition
  • Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
Keywords
human neutrophil elastase, elastase inhibitors, dihydropyrimidinones, conformational locking, induced fit, chronic obstructive pulmonary disease, acute lung injury, acute respiratory distress syndrome, bronchiectasis, pulmonary hypertension, oral bioavailability, pharmacokinetics, chemical probes
MeSH terms
Dose-Response Relationship, Drug, Freezing, Humans, Lung Diseases, Molecular Conformation, Pyrimidinones, Structure-Activity Relationship, Sulfones, Leukocyte Elastase, Proteinase Inhibitory Proteins, Secretory

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