Novel Sulfonamide Analogs of Sivelestat as Potent Human Neutrophil Elastase Inhibitors

Abstract

Human neutrophil elastase (HNE) is involved in a number of essential physiological processes and has been identified as a potential therapeutic target for treating acute and chronic lung injury. Nevertheless, only one drug, Sivelestat, has been approved for clinical use and just in Japan and the Republic of Korea. Thus, there is an urgent need for the development of low-molecular-weight synthetic HNE inhibitors, and we have developed a wide variety of HNE inhibitors with various chemical scaffolds. We hypothesized that substitution of the active fragment of Sivelestat into these HNE inhibitor scaffolds could modulate their inhibitory activity, potentially resulting in higher efficacy and/or improved chemical stability. Here, we report the synthesis, biological evaluation, and molecular modeling studies of novel compounds substituted with the 4-(sulfamoyl)phenyl pivalate fragment necessary for Sivelestat activity. Many of these compounds were potent HNE inhibitors with activity in the nanomolar range (IC 50 = 19-30 nM for compounds 3a, 3b, 3f, 3g, and 9a), confirming that the 4-(sulfamoyl)phenyl pivalate fragment could substitute for the N-CO group at position 1 and offer a different point of attack for Ser195. Results of molecular docking of the these pivaloyl-containing compounds into the HNE binding site supported the mechanism of inhibitory activity involving a nucleophilic attack of Ser195 from the catalytic triad onto the pivaloyl carbonyl group. Furthermore, some compounds (e.g., 3a and 3f) had a relatively good stability in aqueous buffer (t 1/2 > 9 h). Thus, this novel approach led to the identification of a number of potent HNE inhibitors that could be used as leads for the further development of new therapeutics.

Discovery of New 3,3-Diethylazetidine-2,4-dione Based Thiazoles as Nanomolar Human Neutrophil Elastase Inhibitors with Broad-Spectrum Antiproliferative Activity

“…(Docking for sivelestat was carried out as well and an analogous distance-based cutoff was applied. According to reference [ 39 ], covalent binding occurs involving the carbonyl group; this was accounted for when defining the corresponding cutoff).…”

Ebselen analogues with dual human neutrophil elastase (HNE) inhibitory and antiradical activity

“…This finding is in agreement with previously published results, in which the point of attack of the Ser195 OH of HNE is the terminal ester group of sivelestat. 19 The phagocyte respiratory burst generates reactive oxygen species (ROS) through activation of the NADPH oxidase enzyme, and both receptor-mediated and receptorindependent processes can activate this oxidase. 31,32 Phorbol-12-myristate 13-acetate (PMA) has been used extensively to activate the phagocyte receptor-independent respiratory burst 33,34 and was used here to activate leukocyte ROS production.…”

“…These selenium-containing compounds contained an N-CO group, which we found previously to be responsible for HNE inhibitory activity of all our published compounds, as well as those groups/fragments that gave the best HNE-inhibition in the previous compound series. [19][20][21] We also investigated the effects of adding other groups, such as urea and carbamate, and a fragment of the drug sivelestat (4-(sulfamoyl)phenyl pivalate), resulting in the first small series of seleno derivatives (red circle in Fig. 1).…”

Human neutrophil elastase inhibitors: Classification, biological‐synthetic sources and their relevance in related diseases

“…This type of inhibitor facilitates rapid acylation of the enzyme through ring substitution, offering high stability and potency that contribute to an effective inhibitory mechanism. Typically, these inhibitors exhibit competitive and pseudo-irreversible acyl-enzyme characteristics [61].…”