Synthesis and pharmacological properties of ureidomethylcarbamoylphenylketone derivatives. A new potent and subtype-selective nonpeptide CCK-B/gastrin receptor antagonist, S-0509

Sanji Hagishita, Yasushi Murakami, Kaoru Seno, Susumu Kamata, Nobuhiro Haga, Toshiro Konoike, Yasuhiko Kanda, Ryuichi Kiyama, Takeshi Shiota, Yasunobu Ishihara, Michio Ishikawa, Mayumi Shimamura, Koji Abe, Koji Yoshimura

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1695-1714
Number of pages20
JournalBioorganic and Medicinal Chemistry
Volume5
Issue number8
DOIs
Publication statusPublished - Aug 1 1997
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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