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
| Autor: | Dieter Lang, Ulrich Rosentreter, Franz von Nussbaum, Heike Gielen-Haertwig, Volkhart Min-Jian Li, Michael Gerisch, Martin Bechem, Helmut Haning, Dagmar Karthaus, Leila Telan, Martina Schäfer, Lars Bärfacker, Joachim Mittendorf, Sonja Anlauf, Klemens Lustig, Adrian Tersteegen, Daniel Meibom, Jens Schamberger, Swen Allerheiligen, Fitzgerald Mary F, Stefan Schäfer, Martina Delbeck |
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| Rok vydání: | 2015 |
| Předmět: |
Lung Diseases
ARDS Proteases medicine.medical_treatment Molecular Conformation Proteinase Inhibitory Proteins Secretory biological activity Pyrimidinones Pharmacology Lung injury Biochemistry Structure-Activity Relationship Freezing Drug Discovery medicine Humans Potency Sulfones General Pharmacology Toxicology and Pharmaceutics Protease Dose-Response Relationship Drug Chemistry elastase inhibitors Organic Chemistry Elastase Biological activity Full Papers medicine.disease Pulmonary hypertension biginelli reaction Molecular Medicine proteases Leukocyte Elastase |
| Zdroj: | Chemmedchem |
| ISSN: | 1860-7179 |
| DOI: | 10.1002/cmdc.201500131 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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