Orally active .beta.-lactam inhibitors of human leukocyte elastase-1. Activity of 3,3-diethyl-2-azetidinones
| Autor: | S K, Shah, C P, Dorn, P E, Finke, J J, Hale, W K, Hagmann, K A, Brause, G O, Chandler, A L, Kissinger, B M, Ashe, H, Weston |
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| Rok vydání: | 1992 |
| Předmět: |
Magnetic Resonance Spectroscopy
Stereochemistry Carboxylic acid Molecular Sequence Data Administration Oral Hamster beta-Lactams chemistry.chemical_compound X-Ray Diffraction In vivo Cricetinae Drug Discovery Animals Humans Amino Acid Sequence chemistry.chemical_classification Pancreatic Elastase biology Hydrolysis Biological activity In vitro Enzyme chemistry Enzyme inhibitor Lactam biology.protein Azetidines Molecular Medicine sense organs Leukocyte Elastase |
| Zdroj: | Journal of Medicinal Chemistry. 35:3745-3754 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm00099a003 |
| Popis: | A thorough analysis of the mechanism of inhibition of human leukocyte elastase (HLE) by a monocyclic beta-lactam and the mechanism of beta-lactam hydrolysis led to the preparation of potent and highly stable inhibitors of HLE. This work led to the identification of 4-[(4-carboxyphenyl)-oxy]-3,3-diethyl-1- [[(phenylmethyl)amino]carbonyl]-2-azetidinone (2) as the first orally active inhibitor of human leukocyte elastase (HLE). Analogs of 2 with different substituents on the urea N were synthesized and evaluated for their activity in vitro against HLE as well as in vivo in a hamster lung hemorrhage model. Compounds with a methyl or a methoxy group in the para position of the benzene ring were very potent in both assays. The results are discussed on the basis of the proposed model for the binding of this class of inhibitors to HLE and a possible mechanism of inhibition is presented. |
| Databáze: | OpenAIRE |
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