Inhibition of Human Neutrophil Elastase. 4. Design, Synthesis, X-ray Crystallographic Analysis, and Structure−Activity Relationships for a Series of P2-Modified, Orally Active Peptidyl Pentafluoroethyl Ketones
| Autor: | Herman Schreuder, William A. Metz, R.V. Hoffman, Robert J. Cregge, Farr Robert A, Koehl Jack Roger, Hwa-Ok Kim, Norton P. Peet, Shyam Sunder, S L Durham, M J Janusz, C M Hare, Chantal Tardif, J.T. Pelton, Shujaath Mehdi, S.L. Gallion |
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| Rok vydání: | 1998 |
| Předmět: |
Lung Diseases
Models Molecular Serine Proteinase Inhibitors Ketone Proline Neutrophils Swine Stereochemistry Molecular Conformation Administration Oral Hemorrhage Tripeptide Crystallography X-Ray Chemical synthesis Structure-Activity Relationship Cricetinae Drug Discovery Animals Humans Pancreatic elastase chemistry.chemical_classification Fluorocarbons Binding Sites Pancreatic Elastase biology Chemistry Elastase Active site Ketones Isoquinolines Haloketone Crystallography Enzyme inhibitor Drug Design biology.protein Azetidines Molecular Medicine Leukocyte Elastase Oligopeptides |
| Zdroj: | Journal of Medicinal Chemistry. 41:2461-2480 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm970812e |
| Popis: | A series of P2-modified, orally active peptidic inhibitors of human neutrophil elastase (HNE) are reported. These pentafluoroethyl ketone-based inhibitors were designed using pentafluoroethyl ketone 1 as a model. Rational structural modifications were made at the P3, P2, and activating group (AG) portions of 1 based on structure-activity relationships (SAR) developed from in vitro (measured Ki) data and information provided by modeling studies that docked inhibitor 1 into the active site of HNE. The modeling-based design was corroborated with X-ray crystallographic analysis of the complex between 1 and porcine pancreatic elastase (PPE) and subsequently the complex between 1 and HNE. |
| Databáze: | OpenAIRE |
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