1026438-73-2Relevant academic research and scientific papers
New strategy for antedrug application: Development of metalloproteinase inhibitors as antipsoriatic drugs
Sawa, Masaaki,Tsukamoto, Takako,Kiyoi, Takao,Kurokawa, Kiriko,Nakajima, Fumio,Nakada, Yuichiro,Yokota, Koichi,Inoue, Yoshimasa,Kondo, Hirosato,Yoshino, Kohichiro
, p. 930 - 936 (2002)
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.
Encounter with unexpected collagenase-1 selective inhibitor: Switchover of inhibitor binding pocket induced by fluorine atom
Sawa, Masaaki,Kondo, Hirosato,Nishimura, Shinichiro
, p. 581 - 584 (2007/10/03)
Phosphonamide-based inhibitors having trifluoromethyl moiety showed highly selective inhibition against MMP-1. A possible mechanism of the selectivity of MMP-1 inhibitors through the switchover of the binding pocket was speculated by computational calculations. As a consequence of the unexpected selectivity, the specific interaction of CF3 group of the inhibitor and Arg214 in the S1′ pocket of MMP-1 conducted a low binding energy.
