Chymase leading to tissue remodeling is expected to be a potent
pharmaceutical target. Its functions in vivo are still unclear, because of lack of orally available inhibitors. Recently, however, the
chymase inhibitor
NK3201 (2-(5-formylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-[[3,4-dioxo-1-phenyl-7-(2-pyridyloxy)]-2-heptyl]
acetamide) was demonstrated to have oral activity against neointimal
hyperplasia in dog models (Takai S. et al., Life Sci 69, 1725 - 1732 (2001)). In this review, by showing the efficacy of
NK3201 in some hamster models,
chymase functions in vivo are summarized, and the potency of this
chymase inhibitor is introduced. In vitro study,
NK3201 showed potent
chymase specific inhibitory activity, and Dixon plot analysis indicated competitive inhibition.
Oral administration of
NK3201 into normal rats resulted in rapid spread over every tissue except the brain, and sufficient activity to inhibit tissue
chymase was detected even after 24 h. In passive cutaneous anaphylaxis,
myocardial infarction and
bleomycin-induced
pulmonary fibrosis models, orally administered
NK3201 showed potent inhibition of inflammatory response, tissue
angiotensin II formation, and
fibrosis, respectively. These data suggest that
chymase has a vital role in tissue remodeling through promotion of the inflammatory response, tissue
angiotensin II and tissue
fibrosis. Our recent data indicated
chymase participation in bladder
fibrosis, like
interstitial cystitis. Therefore, the orally active
chymase inhibitor
NK3201 may have protective effects on tissue remodeling in several diseases.