Design and Synthesis of Phosphinamide-Based Hydroxamic Acids as Inhibitors of Matrix Metalloproteinases

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...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1999-01, Vol.42 (1), p.87-94
Main Authors: Pikul, Stanislaw, McDow Dunham, Kelly L, Almstead, Neil G, De, Biswanath, Natchus, Michael G, Anastasio, Melanie V, McPhail, Sara J, Snider, Catherine E, Taiwo, Yetunde O, Chen, Longyin, Dunaway, C. Michelle, Gu, Fei, Mieling, Glen E
Format: Article
Language:English
Subjects:
Binding Sites
Biological and medical sciences
Crystallography, X-Ray
Drug Design
Humans
Hydroxamic Acids - chemical synthesis
Hydroxamic Acids - chemistry
Hydroxamic Acids - metabolism
Hydroxamic Acids - pharmacology
Matrix Metalloproteinase 1
Matrix Metalloproteinase 13
Matrix Metalloproteinase 3 - metabolism
Matrix Metalloproteinase 7
Matrix Metalloproteinase 9
Matrix Metalloproteinase Inhibitors
Medical sciences
Metalloendopeptidases - antagonists & inhibitors
Miscellaneous
Models, Molecular
Organophosphorus Compounds - chemical synthesis
Organophosphorus Compounds - chemistry
Organophosphorus Compounds - metabolism
Organophosphorus Compounds - pharmacology
Pharmacology. Drug treatments
Protease Inhibitors - chemical synthesis
Protease Inhibitors - chemistry
Protease Inhibitors - metabolism
Protease Inhibitors - pharmacology
Recombinant Proteins - antagonists & inhibitors
Stereoisomerism
Structure-Activity Relationship
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Description
Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm980142s