Design and Synthesis of Phosphinamide-Based Hydroxamic Acids as Inhibitors of Matrix Metalloproteinases
| Autor: | Michael George Natchus, Neil Gregory Almstead, Yetunde Olabisi Taiwo, Longyin Chen, Biswanath De, Glen E. Mieling, Sara Johnson Mcphail, Stanislaw Pikul, C. Michelle Dunaway, Catherine E. Snider, Kelly McDow Dunham, and Fei Gu, Melanie V. Anastasio |
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| Rok vydání: | 1998 |
| Předmět: |
Models
Molecular Matrix metalloproteinase inhibitor Stereochemistry Matrix Metalloproteinase Inhibitors Matrix metalloproteinase Crystallography X-Ray Hydroxamic Acids Chemical synthesis Stromelysin 1 Structure-Activity Relationship chemistry.chemical_compound Organophosphorus Compounds Matrix Metalloproteinase 13 Drug Discovery Humans Structure–activity relationship Protease Inhibitors chemistry.chemical_classification Binding Sites Hydroxamic acid biology Metalloendopeptidases Stereoisomerism Recombinant Proteins Enzyme Matrix Metalloproteinase 9 chemistry Enzyme inhibitor Drug Design Matrix Metalloproteinase 7 biology.protein Molecular Medicine Matrix Metalloproteinase 3 Matrix Metalloproteinase 1 |
| Zdroj: | Journal of Medicinal Chemistry. 42:87-94 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | A new series of hydroxamic acid-based matrix metalloproteinase (MMP) inhibitors containing a unique phosphinamide motif derived from D-amino acid was designed, synthesized, and tested for enzyme inhibition. Compounds with an R configuration at phosphorus were found to be potent MMP inhibitors while molecules with the S configuration were almost inactive. Structure-activity relationship studies of the series led to the discovery of the potent inhibitor 16 with IC50 = 20.5 nM and 24.4 nM against fibroblast collagenase (MMP-1) and stromelysin (MMP-3), respectively. The binding mode of this novel phosphinamide-based series of MMP inhibitors was established based on X-ray crystallography of the complex of stromelysin and 16. |
| Databáze: | OpenAIRE |
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