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

doi:10.1016/S0968-0896(97)00104-1

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 journal › Article › peer-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 language	English
Pages (from-to)	1695-1714
Number of pages	20
Journal	Bioorganic and Medicinal Chemistry
Volume	5
Issue number	8
DOIs	https://doi.org/10.1016/S0968-0896(97)00104-1
Publication status	Published - Aug 1997
Externally published	Yes

ASJC Scopus subject areas

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

Access to Document

10.1016/S0968-0896(97)00104-1

Cite this

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, 5(8), 1695-1714. https://doi.org/10.1016/S0968-0896(97)00104-1

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 et al.

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

Research output: Contribution to journal › Article › peer-review

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

@article{3692ea770ec8407bb337ef08725aada3,

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 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.",

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

year = "1997",

month = aug,

doi = "10.1016/S0968-0896(97)00104-1",

language = "English",

volume = "5",

pages = "1695--1714",

journal = "Bioorganic and Medicinal Chemistry",

issn = "0968-0896",

publisher = "Elsevier Limited",

number = "8",

}

TY - JOUR

T1 - Synthesis and pharmacological properties of ureidomethylcarbamoylphenylketone derivatives. A new potent and subtype-selective nonpeptide CCK-B/gastrin receptor antagonist, S-0509

AU - Hagishita, Sanji

AU - Murakami, Yasushi

AU - Seno, Kaoru

AU - Kamata, Susumu

AU - Haga, Nobuhiro

AU - Konoike, Toshiro

AU - Kanda, Yasuhiko

AU - Kiyama, Ryuichi

AU - Shiota, Takeshi

AU - Ishihara, Yasunobu

AU - Ishikawa, Michio

AU - Shimamura, Mayumi

AU - Abe, Koji

AU - Yoshimura, Koji

PY - 1997/8

Y1 - 1997/8

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0030861916&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0030861916&partnerID=8YFLogxK

U2 - 10.1016/S0968-0896(97)00104-1

DO - 10.1016/S0968-0896(97)00104-1

M3 - Article

C2 - 9313871

AN - SCOPUS:0030861916

SN - 0968-0896

VL - 5

SP - 1695

EP - 1714

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

IS - 8

ER -

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

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this