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Nonpeptidic Chymase Inhibitors: Design and Structure-Activity Relationships of Pyrimidinone Derivatives Based on the Predicted Binding Mode of a Peptidic Inhibitor

[ Vol. 9 , Issue. 15 ]

Author(s):

Fumihiko Akahoshi   Pages 1191 - 1199 ( 9 )

Abstract:


While the biological reaction of chymase have been often studied for ten years, the pathophysiological role of chymase has not been fully elucidate due to a lack of effective inhibitors featuring potent inhibitory activity, specificity, and metabolic stability. Recently the discovery of a structurally varied range of novel nonpeptidic inhibitors presents new opportunities to explore the role of chymase under both physiological and pathophysiological conditions and to develop therapeutic agents for chymase-induced diseases. In this article the structure and the inhibitory mechanism of nonpeptidic chymase inhibitors are discussed, with special emphasis on design and structure-activity relationships of pyrimidinone derivative where inhibitory activity, protease selectivity, and pharmacokinetic profile are clarified.

Keywords:

nonpeptidic chymase inhibitors, pyrimidinone derivatives, peptidic inhibitor, nonpeptidic inhibitors, pyrimidinone derivative

Affiliation:

Research Laboratory II,Research and Development Division, Mitsubishi Pharma Corporation, 1000,Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan.



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