Abstract
Compounds that can effectively inhibit the proteolytic activity of human neutrophil elastase (HNE) represent promising therapeutics for treatment of inflammatory diseases. We present here the synthesis, structure–activity relationship analysis, and biological evaluation of a new series of HNE inhibitors with a cinnoline scaffold. These compounds exhibited HNE inhibitory activity but had lower potency compared to N-benzoylindazoles previously reported by us. On the other hand, they exhibited increased stability in aqueous solution. The most potent compound, 18a, had a good balance between HNE inhibitory activity (IC50 value = 56 nM) and chemical stability (t1/2 = 114 min). Analysis of reaction kinetics revealed that these cinnoline derivatives were reversible competitive inhibitors of HNE. Furthermore, molecular docking studies of the active products into the HNE binding site revealed two types of HNE inhibitors: molecules with cinnolin-4(1H)-one scaffold, which were attacked by the HNE Ser195 hydroxyl group at the amido moiety, and cinnoline derivatives containing an ester function at C-4, which is the point of attack of Ser195.
Highlights
Human neutrophil elastase (HNE) is a serine protease belonging to the chymotrypsin family and is stored in azurophilic granules of neutrophils where, with other serine proteases, it participates in the oxygen-independent pathway of intracellular and extracellular pathogen destruction[1,2]
Alterations in the balance between HNE activity and its regulatory inhibitors have been implicated in the development of a variety of diseases affecting the pulmonary system, such as chronic obstructive pulmonary disease (COPD)[9], cystic fibrosis (CF)[10,11], acute respiratory distress syndrome (ARDS)[12], acute lung injury (ALI)[13], as well as other inflammatory disorders, such as psoriasis, dermatitis, atherosclerosis, and rheumatoid arthritis[14,15,16]
Compound 3, which was previously described[30], is the key intermediate for final compounds 4–7. It was synthesized starting from precursor 129, which was treated with diethylcarbonate and NaH (2) and transformed into the 4-oxo-1,4-dihydrocinnoline 3 (30) by cyclization with trifluoracetic acid
Summary
Human neutrophil elastase (HNE) is a serine protease belonging to the chymotrypsin family and is stored in azurophilic granules of neutrophils where, with other serine proteases, it participates in the oxygen-independent pathway of intracellular and extracellular pathogen destruction[1,2]. Due to its proteolytic activity against a variety of extracellular matrix proteins, such as elastin, fibronectin, collagen, proteoglycans, laminin[4], and some matrix metalloproteinases (i.e. MMP-2, MMP-3, and MMP-9)[5], HNE plays an important role in many physiological processes, such as blood coagulation, apoptosis, and inflammation, and is able to modulate cytokine and growth factors expression[6]. Alterations in the balance between HNE activity and its regulatory inhibitors have been implicated in the development of a variety of diseases affecting the pulmonary system, such as chronic obstructive pulmonary disease (COPD)[9], cystic fibrosis (CF)[10,11], acute respiratory distress syndrome (ARDS)[12], acute lung injury (ALI)[13], as well as other inflammatory disorders, such as psoriasis, dermatitis, atherosclerosis, and rheumatoid arthritis[14,15,16]. It is evident that compounds able to modulate the proteolytic activity of HNE could represent promising therapeutic agents for the treatment of inflammatory diseases involving excessive HNE activity[20,21]
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