title: Synthesis and pharmacological properties of ureidomethylcarbamoylphenylketone derivatives. A new potent and subtype-selective nonpeptide CCK-B/gastrin receptor antagonist, S-0509.
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 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.
authors.affiliation: Shionogi Research Laboratories, Shionogi & Co., Ltd, Osaka, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Hagishita
authors.forename: Y
authors.initials: Y
authors.lastname: Murakami
authors.forename: K
authors.initials: K
authors.lastname: Seno
authors.forename: S
authors.initials: S
authors.lastname: Kamata
authors.forename: N
authors.initials: N
authors.lastname: Haga
authors.forename: T
authors.initials: T
authors.lastname: Konoike
authors.forename: Y
authors.initials: Y
authors.lastname: Kanda
authors.forename: R
authors.initials: R
authors.lastname: Kiyama
authors.forename: T
authors.initials: T
authors.lastname: Shiota
authors.forename: Y
authors.initials: Y
authors.lastname: Ishihara
authors.forename: M
authors.initials: M
authors.lastname: Ishikawa
authors.forename: M
authors.initials: M
authors.lastname: Shimamura
authors.forename: K
authors.initials: K
authors.lastname: Abe
authors.forename: K
authors.initials: K
authors.lastname: Yoshimura
mesh_terms: 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
chemical_list: D001577:Benzophenones; D010671:Phenylurea Compounds; D043886:Receptor, Cholecystokinin A; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; C109118:S 0509; D010418:Pentagastrin