Abstract
Phosphonamide-based inhibitors were synthesized and evaluated for the inhibitory activities against the shedding of epidermal growth factors, amphiregulin and heparin-binding EGF-like growth factor, that would participate in the development of psoriasis. All compounds exhibited excellent inhibitory activities for these EGF sheddings; however, they also inhibited matrix metalloproteinases (MMPs). To avoid adverse effects reported by the clinical development of MMP inhibitors, the antedrug concept was introduced. Among the phosphonamide inhibitors, the 2,2,2-trifluoroethyl ester 8d and 2,2-difluoroethyl ester 8c showed rapid decomposition in human plasma, which is an essential property for the antedrug. Topical applications of these compounds significantly suppressed TPA-induced epidermal hyperplasia in murin skin, a model of psoriasis. These results suggested that the phosphonamide-based inhibitors have a therapeutic potential for the treatment of psoriasis as an antedrug application.
MeSH terms
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Amphiregulin
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Animals
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Cell Line
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Disease Models, Animal
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Drug Stability
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EGF Family of Proteins
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Epidermal Growth Factor / antagonists & inhibitors
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Glycoproteins / antagonists & inhibitors
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Growth Substances
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Heparin-binding EGF-like Growth Factor
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Humans
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Hydroxylamines / blood
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Hydroxylamines / chemical synthesis*
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Hydroxylamines / pharmacology
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Hyperplasia / chemically induced
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Intercellular Signaling Peptides and Proteins*
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Isoquinolines / blood
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Isoquinolines / chemical synthesis*
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Isoquinolines / pharmacology
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Magnetic Resonance Spectroscopy
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Matrix Metalloproteinase Inhibitors
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Metalloendopeptidases / antagonists & inhibitors*
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Mice
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Protease Inhibitors / blood
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Protease Inhibitors / chemical synthesis*
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Protease Inhibitors / pharmacology
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Psoriasis / chemically induced
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Psoriasis / pathology
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Recombinant Proteins / chemistry
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Skin / drug effects
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Skin / pathology
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Tetradecanoylphorbol Acetate
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Tetrahydroisoquinolines*
Substances
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AREG protein, human
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Amphiregulin
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Areg protein, mouse
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EGF Family of Proteins
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Glycoproteins
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Growth Substances
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HBEGF protein, human
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Hbegf protein, mouse
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Heparin-binding EGF-like Growth Factor
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Hydroxylamines
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Intercellular Signaling Peptides and Proteins
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Isoquinolines
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Matrix Metalloproteinase Inhibitors
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N-hydroxy-2-((2,2,2-trifluoroethoxy)(4-methoxyphenyl)phosphoryl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide
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N-hydroxy-2-((2,2-difluoroethoxy)(4-methoxyphenyl)phosphoryl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide
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Protease Inhibitors
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Recombinant Proteins
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Tetrahydroisoquinolines
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Epidermal Growth Factor
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Metalloendopeptidases
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Tetradecanoylphorbol Acetate