Title of article :
Synthesis and pharmacological properties of ureidomethylcarbamoylphenylketone derivatives. A new potent and subtype-selective nonpeptide CCK-B/gastrin receptor antagonist, S-0509 Original Research Article
Author/Authors :
Sanji Hagishita، نويسنده , , Yasushi Murakami، نويسنده , , Kaoru Seno، نويسنده , , Susumu Kamata، نويسنده , , Nobuhiro Haga، نويسنده , , Toshiro Konoike*، نويسنده , , Yasuhiko Kanda، نويسنده , , Ryuichi Kiyama، نويسنده , , Takeshi Shiota، نويسنده , , Yasunobu Ishihara، نويسنده , , Michio Ishikawa، نويسنده , , Mayumi Shimamura، نويسنده , , Koji Abe، نويسنده , , Koji Yoshimura، نويسنده ,
Abstract :
A novel series of CCK-B/gastrin receptor antagonists—ureidomethylcarbamoylphenylketone derivatives—were designed, synthesized, and evaluated for activity. Structure-activity relationship studies revealed the importance of a carboxylic acid at substituent R2 and a tert-butoxycarbonyl group at R1 in structure A. Compound 7a (S-0509) showed remarkable affinity for the CCK-B/gastrin receptor and a subtype selectivity profile in vitro. Administration (id) of 7a led to excellent inhibition of gastric acid secretion induced by pentagastrin in anesthetized rats with an ED50 value of 0.014 mg/kg. Furthermore, 7a proved to have poor blood-brain permeability by its small effect on enhancement of morphine analgesia. Thus, S-0509 has an increase in selectivity for the peripheral effects of gastrin antagonism from the central effects of CCK-B antagonism.
