Neutrophil elastase inhibitors: a patent review and potential applications for inflammatory lung diseases (2010 – 2014)

Abstract

According to this review of recent NE inhibitor patents, all of the disclosed inhibitors can be classified into peptide- and non-peptide-based groups. The non-peptide NE inhibitors include heterocyclics, uracil derivatives and deuterium oxide. Among the heterocyclic analogs, derivatives of pyrimidinones, tetrahydropyrrolopyrimidinediones, pyrazinones, benzoxazinones and hypersulfated disaccharides were introduced. The literature has increasingly implicated NE in the pathogenesis of various diseases, of which inflammatory destructive lung diseases remain a major concern. However, only a few agents have been validated for therapeutic use in clinical settings to date.

SERPINB1 ameliorates acute lung injury in liver transplantation through ERK1/2-mediated STAT3-dependent HO-1 induction

“…As shown in Fig.2, 6 hours after OALT, HPX was significantly reduced while ACTG2 and SERPINB1 were elevated. Given that SERPINB1 was the inhibitor of neutrophil elastase which plays an important role in ALI 24,25 , and that SERPINB1 was the only one of the top 3 proteins correlated with ALI that changed in both 2 hours and 6 hours post-OALT, we then evaluated the changes of mRNA and protein expressions of pulmonary SERPINB1 in different time points after OALT. As shown in Fig.2D-E, both pulmonary mRNA and protein levels of SERPINB1 were increased after OALT from 4 hours to 48 hours compared to that in respective sham groups and peaked at 8 hours after OALT.…”

Interactions between Neutrophils and Pseudomonas aeruginosa in Cystic Fibrosis

“…While several excellent reviews provide deeper insight into this field, here, only the main approaches will be mentioned [195,196,197,198]. Inhibition of NE represents a rather classical approach to diminish PMN-mediated lung damage in CF [199,200,201]. Phosphodiesterase (PDE4) inhibitors reduce cAMP synthesis and thereby have direct inhibitory action on inflammatory cell signaling and PMN recruitment [195].…”

The past decade in bench research into pulmonary infectious diseases: What do clinicians need to know?

“…Neutrophils are the most abundant inflammatory cell in chronic lung diseases such as COPD, bronchiectasis and CF, but studies aiming to reduce neutrophil recruitment to the airway with LTB4 receptor antagonists, CXCR2 antagonists and neutrophil elastase inhibitors have also been unsuccessful (or too small or short term to determine their effectiveness). 70,71 Preventing neutrophil recruitment in infectious lung diseases is likely to be unhelpful because neutrophils are required for control of bronchial infection, as illustrated by the significant adverse events associated with LTB4 antagonism in CF. 72 Phosphoinositide 3-kinases (PI3K) control migration and activation of neutrophils and are considered potential targets for neutrophil modulator drugs, particularly in COPD and asthma.…”