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Freezing the Bioactive Conformation to Boost Potency: The Identification of BAY85-8501, a Selective and Potent Inhibitor of Human Neutrophil Elastase for Pulmonary Diseases
Ist Teil von
ChemMedChem, 2015-07, Vol.10 (7), p.1163
Ort / Verlag
Weinheim: Wiley Subscription Services, Inc
Erscheinungsjahr
2015
Link zum Volltext
Quelle
Wiley Online Library
Beschreibungen/Notizen
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. BAY85-8501 ((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. BAY85-8501 is currently being tested in clinical studies for the treatment of pulmonary diseases.