Development of a chymase inhibitor: pharmacological characterization of a chymase inhibitor in inflamed tissue remodeling and fibrosis.
Chymase, a chymotrypsin-like serine protease, has not only alternative angiotensin II-generating activity but also various activities involving inflammatory responses. However, little is known of its contribution to physiological functions. Therefore, chymase inhibitors are thought to be potentially useful as tools for elucidating the physiological functions of chymase and therapeutic agents. Within the last five years, many patents on non-peptide chymase inhibitors have been published. We developed a potent non-peptide chymase inhibitor BCEAB (4-[1-[[bis-(4-methyl-phenyl)-methy]-carbamoyl]-3-(2-ethoxy-benzyl)-4-oxo-azetidine-2-yloxy]-benzoic acid) and examined its effect on inflamed tissue remodeling and fibrosis using a hamster sponge implant model. BCEAB has high inhibitory activity against human chymase but not against angiotensin-converting enzyme, elastase and tryptase. In the hamster sponge implant model, oral administration of BCEAB for 15 days dose-dependently suppressed both the dry weight of granuloma tissues in the sponge discs and the amounts of hydroxyproline in the tissues gradually increased during the experimental period. These results suggest that chymase, at least in part, participates in the growth of granuloma tissues of inflammatory regions by stimulating fibroblast growth and extracellular matrix collagen deposition. Chymase inhibitors for oral administration, such as BCEAB, might be useful for clarifying the pathophysiological roles of chymase in vivo.
Nakajima
Masatoshi
M
Discovery Research Laboratories, Shionogi & Co., Ltd., Toyonaka, Osaka, Japan. masatoshi.nakajima@shionogi.co.jp
Naya
Noriyuki
N
D000284:Administration, Oral; D000818:Animals; D001384:Azetidines / Q000494:pharmacology* / Q000627:therapeutic use; D001565:Benzoates / Q000494:pharmacology* / Q000627:therapeutic use; D053818:Chymases; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005355:Fibrosis / Q000188:drug therapy / Q000201:enzymology*; D007249:Inflammation / Q000188:drug therapy / Q000201:enzymology*; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use
C439760:4-(1-((bis(4-methylphenyl)methyl)carbamoyl)-3-(2-ethoxybenzyl)-4-oxoazetidine-2-yloxy)benzoic acid; D001384:Azetidines; D001565:Benzoates; D015842:Serine Proteinase Inhibitors; D012697:Serine Endopeptidases; D053818:Chymases