Shigeki Kuwahara

Syntheses and evaluation of amidinobenzofuran derivatives as tryptase inhibitors.

We report the syntheses and evaluation of amidinobenzofuran derivatives as tryptase inhibitors. Among the compounds we evaluated, 1,5-Bis[4-(5-amidinobenzofuran-2-ylcarbonyl)piperazinylca rbonylmethoxy]cyclooctane 26 (AY0068) was found to be a selective and potent non-peptide inhibitor. 26 was effective in PCA reaction in rats without showing antihistaminic activity.

Non-peptidic inhibitors of human chymase. Synthesis, structure-activity relationships, and pharmacokinetic profiles of a series of 5-amino-6-oxo-1, 6-dihydropyrimidine-containing trifluoromethyl ketones

Chymase possesses a wide variety of actions, including promotion of angiotensin II production and histamine release from mast cells. However, due to a lack of effective inhibitors featuring both high inhibitory activity and high metabolic stability, the pathophysiological role of chymase has not been fully elucidated. We designed non-peptidic inhibitors based on the predicted binding mode of the peptidic chymase inhibitor Val-Pro-Phe-CF3 and demonstrated that the Val-Pro unit is replaceable with a (5-amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl)acetyl moiety. Structure-activity relationship studies revealed that phenyl substitution at the 2-position of the pyrimidinone ring is indispensable for high activity. The most potent compound 1h (Ki = 0.0506 microM) is superior in potency to the parent peptidic inhibitor Val-Pro-Phe-CF3 and has good selectivity for chymase over other proteases. The related analogue 1e was orally absorbed and maintained high plasma levels for at least 2h. These results suggest that the derivatives reported here could be developed as agents for treatment of chymase-induced disease.