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New strategy for antedrug application: development of metalloproteinase inhibitors as antipsoriatic drugs.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2002 Feb 14; Vol. 45 (4), pp. 930-6. - Publication Year :
- 2002
-
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.
- Subjects :
- Amphiregulin
Animals
Cell Line
Disease Models, Animal
Drug Stability
EGF Family of Proteins
Epidermal Growth Factor antagonists & inhibitors
Glycoproteins antagonists & inhibitors
Growth Substances
Heparin-binding EGF-like Growth Factor
Humans
Hydroxylamines blood
Hydroxylamines pharmacology
Hyperplasia chemically induced
Isoquinolines blood
Isoquinolines pharmacology
Magnetic Resonance Spectroscopy
Matrix Metalloproteinase Inhibitors
Mice
Protease Inhibitors blood
Protease Inhibitors pharmacology
Psoriasis chemically induced
Psoriasis pathology
Recombinant Proteins chemistry
Skin drug effects
Skin pathology
Tetradecanoylphorbol Acetate
Hydroxylamines chemical synthesis
Intercellular Signaling Peptides and Proteins
Isoquinolines chemical synthesis
Metalloendopeptidases antagonists & inhibitors
Protease Inhibitors chemical synthesis
Tetrahydroisoquinolines
Subjects
Details
- Language :
- English
- ISSN :
- 0022-2623
- Volume :
- 45
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 11831905
- Full Text :
- https://doi.org/10.1021/jm010349c