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.

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In this paper, we discuss various methods for fraction collection in high-throughput chromatography. UV-triggered fractionation allows precise cutting of peaks. However, valuable fraction collector space is wasted, because many undesired compounds are collected. In mass-triggered fraction collection, the collector space is used more efficiently, because only peaks containing the desired products are collected. Unfortunately, mass peaks are broader than UV peaks, and therefore, fractions contaminated by a closely following peak are often collected. This can be avoided if the collection in preparative LC/MS occurs by a logical AND combination of UV- and mass-triggered collection. The success of this optimal collection mode is shown for three examples.

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