Novel 5-Hydroxytryptamine (5-HT_3) Receptor Antagonists. I. Synthesis and Structure-Activity Relationships of Conformationally Restricted Fused Imidazole Derivatives

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概要

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• We prepared a novel series of conformationally restricted fused imidazole derivatives 4b, 4c and 4d (possessing 4,5,6,7-tetrahydroimidazo[4,5-c]pyridine and substituted 4,5,6,7-tetrahydro-1H-benzimidazole for 4b, 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine for 4c and 5,6,7,8-tetrahydroimidazo[1,5-a]pyridine for 4d as a basic amine part and (2-methoxyphenyl)aminocarbonyl group as an aromatic-carbonyl part). Their activities were then evaluated as an 5-hydroxytryptamine (5-HT_3) receptor antagonist which may be useful for the treatment of irritable bowel syndrome (IBS) as well as for nausea and vomiting associated with cancer chemotherapy. The most potent compound was N-(2-methoxyphenyl)-4,5,6,7-tetrahydro-1H-benzimidazole-5-carboxamide 14 in this series with an ID_<50> value of 0.32 μg/kg on the von Benzold-Jarisch reflex in rats and an IC_<50> value of 0.43 μM on the isolated colonic contraction in guinea pig, approximately ten and two times more potent than ondansetron 1,respectively. The structure-activity relationships (SAR) study suggested that the high potency of 14 may be attributed to the suitable position and direction of the N-C-N centroid in the conformationally restricted imidazole ring against the planar (2-methoxy-phenyl)aminocarbonyl part in the binding of 14 to the receptor.

• 公益社団法人日本薬学会の論文
• 1996-05-15

著者

• 斎藤 徹

  Faculty Of Pharmaceutical Sciences Kanazawa University

• Miyata K

  Yamanouchi Pharmaceutical Co. Ltd. Ibaraki Jpn

• Miyata K

  Yamanouchi Pharmaceutical Co. Ltd. Tsukuba City Jpn

• Miyata Keiji

  Inflammation Research Pharmacology Laboratories Institute For Drug Discovery Research Yamanouchi Pha

• Suzuki T

  Drug Discovery Research Laboratory Sanwa Kagaku Kenkyusho Co. Ltd.

• 増田 明

  富山医科薬科大学麻酔科

• Suzuki T

  Laboratory Of Biopharmaceutics Faculty Of Pharmaceutical Sciences Chiba University

• Ohta Masato

  Pharmaceutical Research Center Meiji Seika Kaisha Ltd.

• Yanagisawa I

  Yamanouchi Pharmaceutical Co. Ltd. Ibaraki Jpn

• Yanagisawa Isao

  Institute For Drug Discovery Research Yamanouchi Pharmaceutical Co.

• Yanagisawa Isao

  山之内製薬

• Saito Takako

  Research And Development Laboratories Maruho Co. Ltd.

• Matsuhisa Akira

  Gastrointestinal Research Laboratories Institute For Drug Discovery Research Yamanouchi Pharmaceutic

• Suzuki Toshikazu

  Discovery Research Laboratory Tanabe Seiyaku Co. Ltd.

• Ohta Miyako

  Division Of Biological Chemistry And Biologicals National Institute Of Health Sciences

• Miyata K

  Institute For Drug Discovery Research Yamanouchi Pharmaceutical Co.

• Ohta Mitsuaki

  Neuroscience/gastrointestinal Research Laboratories Institute For Drug Discovery Research Yamanouchi

• Furuya T

  Yamanouchi Pharmaceutical Co. Ltd. Ibaraki Jpn

• Furuya Toshio

  Lead Discovery Laboratories Institute For Drug Discovery Research Yamanouchi Pharmaceutical Co. Ltd.

• Koide T

  Hiroshima Univ. Higashi‐hiroshima‐shi Jpn

• Miyata K

  Inflammation Research Pharmacology Laboratories Institute For Drug Discovery Research Yamanouchi Pha

• Suzuki T

  Research Unit Of Pharmaceutics College Of Pharmacy Nihon University

• Miyata K

  Hitachi Research Laboratory Hitachi Ltd.

• SUZUKI Takeshi

  Gastrointestinal Research Laboratories Institute for Drug Discovery Research, Yamanouchi Pharmaceuti

• FURUYA Toshio

  Neuroscience

• KOIDE Tokuo

  Neuroscience

• MIYATA Keiji

  Gastrointestinal Research Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceut

• YANAGISAWA Isao

  Neuroscience

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