ONO-5046, a novel inhibitor of human neutrophil elastase
Abstract
ONO-5046, N-[2-[4-(2,2-Dimethylpropionyloxy)phenylsulfonylamino] aminoacetic acid, competitively inhibited human neutrophil elastase (IC50 = 0.044 microM, Ki = 0.2 microM). It also inhibited leukocyte elastase obtained from rabbit, rat, hamster and mouse. However, ONO-5046 did not inhibit trypsin, thrombin, plasmin, plasma kallikrein, pancreas kallikrein, chymotrypsin and cathepsin G even at 100 microM. In in vivo studies, ONO-5046 suppressed lung hemorrhage in hamster (ID50 = 82 micrograms/kg) by intratracheal administration and increase of skin capillary permeability in guinea pig (ID50 = 9.6 mg/kg) by intravenous administration, both of which were induced by human neutrophil elastase.
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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 [22]
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 [22]
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- Authors
- Kawabata, K., Suzuki, M., Sugitani, M., Imaki, K., Toda, M., & Miyamoto, T.
- Affiliations
- Ono Pharmaceutical (Japan) (JP)
- ORCID
- Suzuki, Mayumi
- Venue
- Biochemical and Biophysical Research Communications
- Publisher
- Elsevier BV
- Published
- 1991-06
- Volume
- 177
- Issue
- 2
- Pages
- 814-820
- ISSN
- 0006-291X (ISSN-L)
- OpenAlex
- W2039697569
- Cited by
- 359
- References
- 13
- Citations by year
- 2026: 8 · 2025: 6 · 2024: 11 · 2023: 10 · 2022: 10 · 2021: 9 · 2020: 7 · 2019: 9 · 2018: 7 · 2017: 8 · 2016: 8 · 2015: 18 · 2014: 8 · 2013: 11 · 2012: 12
- FWCI
- 2.09
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemical and Biophysical Research Communications (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Health Sciences › Medicine › Genetics › Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Keywords
- ONO-5046, human neutrophil elastase, leukocyte elastase, elastase inhibitors, competitive inhibition, serine protease inhibition, pulmonary hemorrhage
- MeSH terms
- Animals, Binding, Competitive, Capillary Permeability, Glycine, Guinea Pigs, Cricetinae, Hemorrhage, Humans, Lung Diseases, Male, Mesocricetus, Neutrophils, Pancreatic Elastase, Rabbits, Skin Diseases, Sulfonamides, Mice, Rats
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