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

• Published in: Journal of medicinal chemistry Vol. 42; no. 1; pp. 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: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 14-01-1999
• 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; Human; Stromelysin 1; Enzyme; Hydroxamic acid; Enzyme inhibitor; Metalloendopeptidases; Inhibitor enzyme complex; In vitro; Modeling; Phosphorus Organic compounds; Peptidases; α-Aminoacid; Structure activity relation; Hydrolases; R configuration; Chemical synthesis; Interstitial collagenase
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm980142s

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.