Synthesis and pharmacological properties of ureidomethylcarbamoylphenylketone derivatives. A new potent and subtype-selective nonpeptide CCK-B/gastrin receptor antagonist, S-0509.
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 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.
Hagishita
S
S
Shionogi Research Laboratories, Shionogi & Co., Ltd, Osaka, Japan.
Murakami
Y
Y
Seno
K
K
Kamata
S
S
Haga
N
N
Konoike
T
T
Kanda
Y
Y
Kiyama
R
R
Shiota
T
T
Ishihara
Y
Y
Ishikawa
M
M
Shimamura
M
M
Abe
K
K
Yoshimura
K
K
D000818:Animals; D001577:Benzophenones / Q000138:chemical synthesis* / Q000494:pharmacology; D005744:Gastric Acid / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D010418:Pentagastrin / Q000037:antagonists & inhibitors; D010671:Phenylurea Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043886:Receptor, Cholecystokinin A; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D001577:Benzophenones; D010671:Phenylurea Compounds; D043886:Receptor, Cholecystokinin A; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; C109118:S 0509; D010418:Pentagastrin