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.