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 journalArticle

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 1997
Externally publishedYes

Fingerprint

S 0509
Cholecystokinin B Receptor
Pharmacology
Derivatives
Pentagastrin
Gastrins
Carboxylic Acids
Morphine
Rats
Brain
Blood
Acids
Gastric Acid
Structure-Activity Relationship
Analgesia
Permeability

ASJC Scopus subject areas

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

Cite this

Synthesis and pharmacological properties of ureidomethylcarbamoylphenylketone derivatives. A new potent and subtype-selective nonpeptide CCK-B/gastrin receptor antagonist, S-0509. / Hagishita, Sanji; Murakami, Yasushi; Seno, Kaoru; Kamata, Susumu; Haga, Nobuhiro; Konoike, Toshiro; Kanda, Yasuhiko; Kiyama, Ryuichi; Shiota, Takeshi; Ishihara, Yasunobu; Ishikawa, Michio; Shimamura, Mayumi; Abe, Koji; Yoshimura, Koji.

In: Bioorganic and Medicinal Chemistry, Vol. 5, No. 8, 08.1997, p. 1695-1714.

Research output: Contribution to journalArticle

Hagishita, S, Murakami, Y, Seno, K, Kamata, S, Haga, N, Konoike, T, Kanda, Y, Kiyama, R, Shiota, T, Ishihara, Y, Ishikawa, M, Shimamura, M, Abe, K & Yoshimura, K 1997, 'Synthesis and pharmacological properties of ureidomethylcarbamoylphenylketone derivatives. A new potent and subtype-selective nonpeptide CCK-B/gastrin receptor antagonist, S-0509', Bioorganic and Medicinal Chemistry, vol. 5, no. 8, pp. 1695-1714. https://doi.org/10.1016/S0968-0896(97)00104-1
Hagishita, Sanji ; Murakami, Yasushi ; Seno, Kaoru ; Kamata, Susumu ; Haga, Nobuhiro ; Konoike, Toshiro ; Kanda, Yasuhiko ; Kiyama, Ryuichi ; Shiota, Takeshi ; Ishihara, Yasunobu ; Ishikawa, Michio ; Shimamura, Mayumi ; Abe, Koji ; Yoshimura, Koji. / Synthesis and pharmacological properties of ureidomethylcarbamoylphenylketone derivatives. A new potent and subtype-selective nonpeptide CCK-B/gastrin receptor antagonist, S-0509. In: Bioorganic and Medicinal Chemistry. 1997 ; Vol. 5, No. 8. pp. 1695-1714.
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