Nonpeptidic chymase inhibitors: design and structure-activity relationships of pyrimidinone derivatives based on the predicted binding mode of a peptidic inhibitor.
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.
Akahoshi
Fumihiko
F
Research Laboratory II, Research and Development Division, Mitsubishi Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan. Akahoshi.Fumihiko@mk.m-pharma.co.jp
D000818:Animals; D053818:Chymases; D015195:Drug Design; D006801:Humans; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D011744:Pyrimidinones / Q000737:chemistry / Q000494:pharmacology*; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D010455:Peptides; D011744:Pyrimidinones; D015842:Serine Proteinase Inhibitors; D012697:Serine Endopeptidases; D053818:Chymases