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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 by Fumihiko Akahoshi; Atsuyuki Ashimori; Takuya Yoshimura; Teruaki Imada; Masahide Nakajima; Naoko Mitsutomi; Shigeki Kuwahara; Tatsuyuki Ohtsuka; Chikara Fukaya; Mizuo Miyazaki; Norifumi Nakamura is a Biochemistry, Genetics and Molecular Biology article available to read on EtoBox.

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AbstractÐChymase possesses a wide variety of actions, including promotion of angiotensin II production and histamine release from mast cells. However, due to a lack of eective 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-CF 3 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 (K i =0.0506 mM) is superior in potency to the parent peptidic inhibitor Val-Pro-Phe-CF 3 and has good selectivity for chymase over other proteases. The related analogue 1e was orally absorbed and maintained high plasma levels for at least 2 h. These results suggest that the derivatives reported here could be developed as agents for treatment of chymase-induced disease.

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Author

Fumihiko Akahoshi; Atsuyuki Ashimori; Takuya Yoshimura; Teruaki Imada; Masahide Nakajima; Naoko Mitsutomi; Shigeki Kuwahara; Tatsuyuki Ohtsuka; Chikara Fukaya; Mizuo Miyazaki; Norifumi Nakamura

Publisher

Elsevier Science; Elsevier ; Elsevier Ltd.; Elsevier BV (ISSN 0968-0896)

Published

2001

Language

EN

Field

Biochemistry, Genetics and Molecular Biology (Life Sciences)