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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
Author(s) -
von Nussbaum Franz,
Li Volkhart M.J.,
Allerheiligen Swen,
Anlauf Sonja,
Bärfacker Lars,
Bechem Martin,
Delbeck Martina,
Fitzgerald Mary F.,
Gerisch Michael,
GielenHaertwig 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
Publication year - 2015
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201500131
Subject(s) - ards , potency , pharmacology , elastase , chemistry , proteases , protease , lung , medicine , stereochemistry , biochemistry , enzyme , in vitro
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.