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

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 respir...

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Published in:ChemMedChem 2015-07, Vol.10 (7), p.1163-1173
Main Authors: von Nussbaum, Franz, Li, Volkhart M.-J., Allerheiligen, Swen, Anlauf, Sonja, Bärfacker, Lars, Bechem, Martin, Delbeck, Martina, Fitzgerald, Mary F., Gerisch, Michael, Gielen-Haertwig, Heike, Haning, Helmut, Karthaus, Dagmar, Lang, Dieter, Lustig, Klemens, Meibom, Daniel, Mittendorf, Joachim, Rosentreter, Ulrich, Schäfer, Martina, Schäfer, Stefan, Schamberger, Jens, Telan, Leila A., Tersteegen, Adrian
Format: Article
Language:English
Subjects:
biginelli reaction
biological activity
Dose-Response Relationship, Drug
elastase inhibitors
Freezing
Humans
Leukocyte Elastase - antagonists & inhibitors
Leukocyte Elastase - metabolism
Lung Diseases - enzymology
Molecular Conformation
proteases
Proteinase Inhibitory Proteins, Secretory - chemistry
Proteinase Inhibitory Proteins, Secretory - pharmacology
pyrimidinones
Pyrimidinones - chemistry
Pyrimidinones - pharmacology
Structure-Activity Relationship
Sulfones - chemistry
Sulfones - pharmacology
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Summary: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. Breathe better: It′s as potent as a low‐molecular‐weight inhibitor can get! Human neutrophil elastase (HNE) is a driver of pulmonary diseases. We describe the discovery of BAY 85‐8501, a small‐molecule inhibitor with picomolar in vitro potency against HNE. BAY 85‐8501 is currently being assessed in clinical studies for pulmonary diseases.
ISSN:1860-7179
1860-7187
DOI:10.1002/cmdc.201500131