Document Report Card

ID: ALA1135982

Journal: J Med Chem

Title: New strategy for antedrug application: development of metalloproteinase inhibitors as antipsoriatic drugs.

Authors: Sawa M, Tsukamoto T, Kiyoi T, Kurokawa K, Nakajima F, Nakada Y, Yokota K, Inoue Y, Kondo H, Yoshino K.

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.

CiteXplore: 11831905

DOI: 10.1021/jm010349c