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.

New Advances on the Functions of Epidermal Growth Factor Receptor and Ceramides in Skin Cell Differentiation, Disorders and Cancers

“…Among EGFR tyrosine kinase inhibitors, AG-1571 (SU-5271) and AG1478 have been observed to potently inhibit the proliferation of psoriatic keratinocytes [91,92,97,98]. Moreover, topical application of phosphonamidebased inhibitors of shedding EGF-like ligands has revealed that these drugs suppress epidermal hyperplasia and could, therefore, represent interesting adjuvant therapeutic agents for the treatment of psoriasis [98].…”

“…Moreover, topical application of phosphonamidebased inhibitors of shedding EGF-like ligands has revealed that these drugs suppress epidermal hyperplasia and could, therefore, represent interesting adjuvant therapeutic agents for the treatment of psoriasis [98]. However, additional in vitro characterization of different models and clinical trials are needed to define specific skin disorders where topical application of formulations containing EGFR inhibitors could be an advantageous treatment.…”

Alteration and Significance of Heparin-Binding Epidermal-Growth-Factor-Like Growth Factor in Psoriatic Epidermis

“…The latter moves to the basal layer and binds with the EGFR on the cytomembrane of basal keratinocytes, not only stimulating the phosphorylation of EGFR, but also inducing the autocrine activity of basal keratinocytes, which yields more sHB-EGF. The latest studies [16]show that metalloproteinase inhibitors such as new antipsoriatic drugs could inhibit the proliferation of epidermis, for metalloproteinase inhibitors can inhibit the conversion from proHB-EGF to sHB-EGF; if this drug is given in early psoriasis, it would be better. Data also reported tyrosine kinase inhibitors as new antipsoriatic drugs to block the activity of EGFR [17], because the proliferation of keratinocytes depended on the path of the ErbB1-tyrosine kinase system.…”

Retrometabolism‐Based Drug Design and Targeting

“…However, because they also inhibited matrix metalloproteinases (MMPs), soft analogs 149 ( Fig. 35) that are susceptible to hydrolytic inactivation were investigated to avoid adverse effects such as the musculoskeletal syndrome of MMP inhibitors [357]. Activity was configuration sensitive: only the (R,R) configuration shown in 149 showed potent inhibition.…”