9SI4
Structure of human neutrophil elastase in complex with a 5,8-dihydro[1,2,4]triazolo[4,3-a]pyrimidin-3(2H)-one inhibitor
This is a non-PDB format compatible entry.
Summary for 9SI4
| Entry DOI | 10.2210/pdb9si4/pdb |
| Descriptor | Neutrophil elastase, alpha-L-fucopyranose-(1-6)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total) |
| Functional Keywords | trypsin family fold, protease, hydrolase, hydrolase-inhibitor complex |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 25055.66 |
| Authors | Rizzi, A.,Armani, E. (deposition date: 2025-08-28, release date: 2025-12-10, Last modification date: 2025-12-24) |
| Primary citation | Armani, E.,Rizzi, A.,Miglietta, D.,Bassanetti, I.,Amadei, F.,Brogin, G.,Capaldi, C.,Rancati, F.,Carnini, C.,Xanxo Fernandez, S.,Civelli, M.,Puccini, P.,Bellini, M.,Jennings, A.,Heald, R.A.,Alcaraz, L.,Sutton, J.M.,Finch, H.,Fitzgerald, M.,Fox, C.,Villetti, G. Design, Synthesis, and Biological Evaluation of the Novel Neutrophil Elastase Inhibitor CHF-6333 for the Inhaled Treatment of Bronchiectasis. J.Med.Chem., 68:24869-24889, 2025 Cited by PubMed Abstract: The inhibitors of neutrophil elastase (NE) have long attracted interest for the treatment of respiratory diseases. We report the breakthrough of a new potent, selective NE inhibitor with a 24 h duration of action: CHF-6333, is currently undergoing clinical studies for the inhaled treatment of bronchiectasis (BE). The story of the discovery project to identify novel small molecules that inhibit extracellular elastase in the lung with prolonged activity is described. Medicinal chemistry investigation, supported by docking studies, led to N-quaternary compounds with an profile suitable for inhalatory administration. Compound emerged from pharmacokinetic and pharmacodynamic studies, also showing safety and no off-target effects . Salt screening of different counterions, in conjunction with local irritancy testing, aided in the selection of compound -xinafoate (CHF-6333). Efficacy in a lung injury model and no findings in non-GLP toxicity studies promoted CHF-6333 as a clinical candidate. PubMed: 41307403DOI: 10.1021/acs.jmedchem.5c02638 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.14 Å) |
Structure validation
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