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

Abstract

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.

Neutrophil elastase inhibitors for the treatment of (cardio)pulmonary diseases: Into clinical testing with pre-adaptive pharmacophores

“…47 75 Compared to the overall promising rodent DMPK profile of the 3 rd and 4 th generation inhibitors, shows a further improved metabolic stability translating into a low clearance and improved half-life with no inhibitory capacity towards CYP isoforms. 76 Studies with have confirmed an anti-inflammatory and anti-remodeling mode of action in preclinical acute and chronic animal models of ALI, PAH, and PH associated with lung emphysema. 76,[80][81][82] Recently, more research groups from industry have been attracted to 5 th generation inhibitiors, leading to further improvements in potency and metabolic stability (20, 23-25, Table 4; Fig.…”

“…76 Studies with have confirmed an anti-inflammatory and anti-remodeling mode of action in preclinical acute and chronic animal models of ALI, PAH, and PH associated with lung emphysema. 76,[80][81][82] Recently, more research groups from industry have been attracted to 5 th generation inhibitiors, leading to further improvements in potency and metabolic stability (20, 23-25, Table 4; Fig. 15).…”

“…In fact, the additional substituent (e.g., SO 2 Me in 21, Fig. 14) 76 raises the rotational barrier at the crucial pyrimidinone-cyanophenyl axis and thereby 'freezes' the structure in an ideal bioactive conformation, thus pre-organizing the inhibitor for the forthcoming binding event. Remarkably, in this case the spatial change that will happen within the target enzyme-upon the induced-fit binding process-is conformationally pre-empted by the inhibitor (pre-adaptive pharmacophore model (Table 2).…”

Human neutrophil elastase inhibitory potential of flavonoids fromCampylotropis hirtellaand their kinetics

“…1D and 2D NMR spectra were recorded on a Bruker (a.m. 500 MHz) spectrometer (Billerica, MA), using Acetone-d 6 , as solvent and tetramethylsilane (TMS) as an internal standard. Electron ionization (EI) and EI high resolution (HR) mass spectra were obtained on a JEOL JMS-700 instrument (JEOL, Tokyo, Japan).…”

“…Most works have focused on the development of synthetic elastase inhibitors that have high potency (IC 50 in the nanomolar range), show selectivity relative to a panel of other proteases and have good metabolic stability. For instance, the BAY 85-8501 is one of best candidate inhibitors for neutrophil elastase 6,7 . However, there are still relatively few studies disclosing natural products that target this important enzyme 8,9 .…”