AUTHOR=Crocetti Letizia , Giovannoni Maria Paola , Cantini Niccolò , Guerrini Gabriella , Vergelli Claudia , Schepetkin Igor A. , Khlebnikov Andrei I. , Quinn Mark T. TITLE=Novel Sulfonamide Analogs of Sivelestat as Potent Human Neutrophil Elastase Inhibitors JOURNAL=Frontiers in Chemistry VOLUME=8 YEAR=2020 URL=https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2020.00795 DOI=10.3389/fchem.2020.00795 ISSN=2296-2646 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 (IC50 = 19–30 nM for compounds