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- 佐藤 正人
- Neuroscience/Gastrointestinal Research Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.
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- 近藤 裕
- Neuroscience/Gastrointestinal Research Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.
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- 岡本 芳典
- Neuroscience/Gastrointestinal Research Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.
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- 西田 明登
- Neuroscience/Gastrointestinal Research Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.
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- 宮田 桂司
- Neuroscience/Gastrointestinal Research Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.
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- 太田 光昭
- Neuroscience/Gastrointestinal Research Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.
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- 間瀬 年康
- Neuroscience/Gastrointestinal Research Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.
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- 村瀬 清志
- Neuroscience/Gastrointestinal Research Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.
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説明
A novel series of 1-aroylmethyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one derivatives was prepared and evaluated for activity as gastrin/cholecystokinin (CCK)-B receptor antagonists. In vitro binding studies showed that some derivatives exhibited potent affinity for gastrin/CCK-B receptor and high selectivity over peripheral CCK (CCK-A) receptor. Furthermore, these compounds potently inhibited pentagastrin-induced gastric acid secretion upon intravenous administration in an in vivo model in rats. Structure-activity relationship studies of this series suggested that 1-[(R)-2,3-dihydro-1-(2-methylphenacyl)-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(3-methylphenyl)urea (35b, YM022) was the optimal compound with IC_<50> values of 0.17,0.11 and 150nM for gastrin, CCK-B and CCK-A receptors, respectively, and an ED_<50> value of 9.5nmol/kg (i.v.) in rats. The absolute configuration of the precursor of YM022,an (R)-3-amino-1,3-dihydro-2H-1,4-benzodiazepin-2-one derivative ((R)-25), was determined by X-ray crystallographic analysis of its (S)-mandelate.It would be expected that YM022,a potent and selective gastrin/CCK-B receptor antagonist, inhibits gastric acid secretion without inducing gastrin-mediated side-effects such as hypergastrinemia and hyperplasia of oxyntic mucosa.
収録刊行物
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- Chemical & pharmaceutical bulletin
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Chemical & pharmaceutical bulletin 43 (12), 2159-2167, 1995-12-01
公益社団法人日本薬学会
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詳細情報 詳細情報について
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- CRID
- 1571417127325134976
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- NII論文ID
- 110003631415
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- NII書誌ID
- AA00602100
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- ISSN
- 00092363
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- 本文言語コード
- en
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- データソース種別
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- CiNii Articles
