title: New strategy for antedrug application: development of metalloproteinase inhibitors as antipsoriatic drugs.
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.
authors.affiliation: Department of Chemistry, R&D Laboratories, Nippon Organon K.K., 1-5-90, Tomobuchi-cho, Miyakojima-ku, Osaka 534-0016, Japan. masaaki-sawa@dainippon-pharm.co.jp
authors.forename: Masaaki
authors.initials: M
authors.lastname: Sawa
authors.forename: Takako
authors.initials: T
authors.lastname: Tsukamoto
authors.forename: Takao
authors.initials: T
authors.lastname: Kiyoi
authors.forename: Kiriko
authors.initials: K
authors.lastname: Kurokawa
authors.forename: Fumio
authors.initials: F
authors.lastname: Nakajima
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Nakada
authors.forename: Koichi
authors.initials: K
authors.lastname: Yokota
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Inoue
authors.forename: Hirosato
authors.initials: H
authors.lastname: Kondo
authors.forename: Kohichiro
authors.initials: K
authors.lastname: Yoshino
mesh_terms: D066258:Amphiregulin; D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D004355:Drug Stability; D066255:EGF Family of Proteins; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors; D006023:Glycoproteins / Q000037:antagonists & inhibitors; D006133:Growth Substances; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D006898:Hydroxylamines / Q000097:blood / Q000138:chemical synthesis* / Q000494:pharmacology; D006965:Hyperplasia / Q000139:chemically induced; D036341:Intercellular Signaling Peptides and Proteins; D007546:Isoquinolines / Q000097:blood / Q000138:chemical synthesis* / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D051379:Mice; D011480:Protease Inhibitors / Q000097:blood / Q000138:chemical synthesis* / Q000494:pharmacology; D011565:Psoriasis / Q000139:chemically induced / Q000473:pathology; D011994:Recombinant Proteins / Q000737:chemistry; D012867:Skin / Q000187:drug effects / Q000473:pathology; D013755:Tetradecanoylphorbol Acetate; D044005:Tetrahydroisoquinolines
chemical_list: C587848:AREG protein, human; D066258:Amphiregulin; C587849:Areg protein, mouse; D066255:EGF Family of Proteins; D006023:Glycoproteins; D006133:Growth Substances; C587883:HBEGF protein, human; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D006898:Hydroxylamines; D036341:Intercellular Signaling Peptides and Proteins; D007546:Isoquinolines; D061965:Matrix Metalloproteinase Inhibitors; C448632:N-hydroxy-2-((2,2,2-trifluoroethoxy)(4-methoxyphenyl)phosphoryl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide; C448633:N-hydroxy-2-((2,2-difluoroethoxy)(4-methoxyphenyl)phosphoryl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide; D011480:Protease Inhibitors; D011994:Recombinant Proteins; D044005:Tetrahydroisoquinolines; D004815:Epidermal Growth Factor; D008666:Metalloendopeptidases; D013755:Tetradecanoylphorbol Acetate