New strategy for antedrug application: Development of metalloproteinase inhibitors as antipsoriatic drugs

Masaaki Sawa, Takako Tsukamoto, Takao Kiyoi, Kiriko Kurokawa, Fumio Nakajima, Yuichiro Nakada, Koichi Yokota, Yoshimasa Inoue, Hirosato Kondo, Kohichiro Yoshino

Research output: Contribution to journalArticle

48 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)930-936
Number of pages7
JournalJournal of Medicinal Chemistry
Volume45
Issue number4
DOIs
Publication statusPublished - Feb 14 2002
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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    Sawa, M., Tsukamoto, T., Kiyoi, T., Kurokawa, K., Nakajima, F., Nakada, Y., Yokota, K., Inoue, Y., Kondo, H., & Yoshino, K. (2002). New strategy for antedrug application: Development of metalloproteinase inhibitors as antipsoriatic drugs. Journal of Medicinal Chemistry, 45(4), 930-936. https://doi.org/10.1021/jm010349c