| Abstract
| - Phosphonamide-based inhibitors were synthesized and evaluated for the inhibitory activitiesagainst the shedding of epidermal growth factors, amphiregulin and heparin-binding EGF-like growth factor, that would participate in the development of psoriasis. All compoundsexhibited excellent inhibitory activities for these EGF sheddings; however, they also inhibitedmatrix metalloproteinases (MMPs). To avoid adverse effects reported by the clinical developmentof 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 inhuman plasma, which is an essential property for the antedrug. Topical applications of thesecompounds significantly suppressed TPA-induced epidermal hyperplasia in murin skin, a modelof psoriasis. These results suggested that the phosphonamide-based inhibitors have atherapeutic potential for the treatment of psoriasis as an antedrug application.
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