Studies on Aromatase Inhibitors. I. Synthesis and Biological Evaluation of 4-Amino-4H-1,2,4-triazole Derivatives
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概要
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Various 4-N-substituted amino-4H-1,2,4-triazole derivatives were synthesized and evaluated for aromatase-inhibitory activity (in vitro) and for pregnant mare serum gonadotropin (PMSG)-induced estrogen synthesis-inhibitory activity (in vivo). The 4-(4-cyanophenyl) amino derivative and 4-(4-nitrophenyl)amino derivative, each possessing a strong electron-withdrawing group on the phenyl moiety, showed potent aromatase-inhibitory activity. Structure-activity relationship studies indicated that 4-[(4-bromobenzyl)(4-cyanophenyl)amino]-4H-1,2,4-triazole (5k, YM511) is a highly potent aromatase inhibitor with IC_<50> values of 0.4 and 0.12 nM in in vitro experiments using rat ovary and human placenta, respectively, and an in vivo ED_<50>of 0.002 mg/kg in rats on oral administration.YM511 was also a weak inhibitor of other steroid hormone synthesis enzymes. These data suggest that YM511 is a highly selective aromatase inhibitor and may be a useful agent for the treatment of estrogen-dependent diseases such as breast cancer.
- 公益社団法人日本薬学会の論文
- 1996-10-15
著者
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Okada M
Institute For Drug Discovery Research Yamanouchi Pharmaceutical Co. Ltd.
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Isomura Y
Yamanouchi Pharmaceutical Co. Ltd. Ibaraki Jpn
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OKADA Minoru
Endocrinology
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YODEN Toru
Metabolic Disease Laboratories Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co.,
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KAWAMINAMI Eiji
Endocrinology
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SHIMADA Yoshiaki
Metabolic Disease Laboratories Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co.,
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KUDOH Masafumi
Endocrinology
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ISOMURA Yasuo
Metabolic Disease Laboratories Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co.,
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SHIKAMA Hisataka
Endocrinology
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FUJIKURA Takashi
Metabolic Disease Laboratories Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co.,
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SHIMADA Yasuo
Mitsuboshi Pharmacutical Co.
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Yoden T
Institute For Technology Development Yamanouchi Pharmaceutical Co. Ltd.
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Shimada Y
Mitsuboshi Pharmaceutical Co
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Kudoh Masafumi
Drug Discovery Research Astellas Pharma Inc.
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Kawaminami Eiji
Medicinal Chemistry Research Ii Institute For Drug Discovery Research Yamanouchi Pharmaceutical Co.
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FURUTANI Takashi
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.
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Furutani Takashi
Drug Discovery Research Astellas Pharma Inc.
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Shikama H
Yamanouchi Pharmaceutical Co. Ltd. Ibaraki Jpn
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