Abstract
The synthesis and structure-activity relationship (SAR) studies of a series of cyclopentane carboxylic acid matrix metalloproteinase (MMP) inhibitors are described. Potent and specific MMP-2, -3, -9, -13 inhibitors were obtained by regio- and stereoselective substitutions at positions 2 and 5 on the cyclopentane ring. Compounds 2a and 2e are active in the mouse B16-F10 metastasis model and display very good pharmacokinetic parameters.
MeSH terms
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Administration, Oral
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Animals
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Biological Availability
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Caco-2 Cells
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Cyclopentanes / chemical synthesis*
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Cyclopentanes / chemistry
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Cyclopentanes / pharmacology
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Humans
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In Vitro Techniques
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Matrix Metalloproteinase Inhibitors*
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Matrix Metalloproteinases / chemistry
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Melanoma, Experimental / drug therapy
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Melanoma, Experimental / pathology
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Mice
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Microsomes, Liver / drug effects
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Microsomes, Liver / metabolism
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Models, Molecular
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Molecular Conformation
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Neoplasm Metastasis
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Permeability
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Phthalimides / chemical synthesis*
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Phthalimides / chemistry
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Phthalimides / pharmacology
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Protease Inhibitors / chemical synthesis*
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Protease Inhibitors / chemistry
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Protease Inhibitors / pharmacology
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Stereoisomerism
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Structure-Activity Relationship
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Triazines / chemical synthesis*
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Triazines / chemistry
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Triazines / pharmacology
Substances
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2-(2-(4'-chlorobiphenylthio))-5-(2-(4-oxo-4H-benzo(d)(1,2,3)triazin-3-ylmethyl))cyclopentanecarboxylic acid
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2-(2-(4'-fluorobiphenyl)ethylthio)-5-(phthalimidomethyl)cyclopentanecarboxylic acid
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Antineoplastic Agents
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Cyclopentanes
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Matrix Metalloproteinase Inhibitors
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Phthalimides
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Protease Inhibitors
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Triazines
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Matrix Metalloproteinases