• Title of article

    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 Original Research Article

  • Author/Authors

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

  • Issue Information
    روزنامه با شماره پیاپی سال 2001
  • Pages
    15
  • From page
    301
  • To page
    315
  • Abstract
    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 μM) 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 2 h. These results suggest that the derivatives reported here could be developed as agents for treatment of chymase-induced disease.
  • Journal title
    Bioorganic and Medicinal Chemistry
  • Serial Year
    2001
  • Journal title
    Bioorganic and Medicinal Chemistry
  • Record number

    1301348