Highlighted Paper selected by Editor-in-Chief : Discovery of a Novel Series of Pyrazolo[1,5-a]pyrimidine-Based Phosphodiesterase 2A Inhibitors Structurally Different from N-((1S)-1-(3-Fluoro-4-(trifluoromethoxy)phenyl)-2-methoxyethyl)-7-methoxy-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide (TAK-915), for the Treatment of Cognitive Disorders
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- Mikami Satoshi
- Pharmaceutical Research Division, Takeda Pharmaceutical Company, Limited
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- Kawasaki Masanori
- Pharmaceutical Research Division, Takeda Pharmaceutical Company, Limited
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- Ikeda Shuhei
- Pharmaceutical Research Division, Takeda Pharmaceutical Company, Limited
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- Negoro Nobuyuki
- Pharmaceutical Research Division, Takeda Pharmaceutical Company, Limited
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- Nakamura Shinji
- Pharmaceutical Research Division, Takeda Pharmaceutical Company, Limited
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- Nomura Izumi
- Pharmaceutical Research Division, Takeda Pharmaceutical Company, Limited
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- Ashizawa Tomoko
- Pharmaceutical Research Division, Takeda Pharmaceutical Company, Limited
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- Kokubo Hironori
- Pharmaceutical Research Division, Takeda Pharmaceutical Company, Limited
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- Hoffman Isaac Dylan
- Takeda California, Inc.
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- Zou Hua
- Takeda California, Inc.
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- Oki Hideyuki
- Pharmaceutical Research Division, Takeda Pharmaceutical Company, Limited
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- Uchiyama Noriko
- Pharmaceutical Research Division, Takeda Pharmaceutical Company, Limited
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- Hiura Yuuto
- Pharmaceutical Research Division, Takeda Pharmaceutical Company, Limited
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- Miyamoto Maki
- Pharmaceutical Research Division, Takeda Pharmaceutical Company, Limited
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- Itou Yuuki
- Pharmaceutical Research Division, Takeda Pharmaceutical Company, Limited
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- Nakashima Masato
- Pharmaceutical Research Division, Takeda Pharmaceutical Company, Limited
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- Iwashita Hiroki
- Pharmaceutical Research Division, Takeda Pharmaceutical Company, Limited
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- Taniguchi Takahiko
- Pharmaceutical Research Division, Takeda Pharmaceutical Company, Limited
書誌事項
- タイトル別名
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- Discovery of a Novel Series of Pyrazolo[1,5-<i>a</i>]pyrimidine-Based Phosphodiesterase 2A Inhibitors Structurally Different from <i>N</i>-((1<i>S</i>)-1-(3-Fluoro-4-(trifluoromethoxy)phenyl)-2-methoxyethyl)-7-methoxy-2-oxo-2,3-dihydropyrido[2,3-<i>b</i>]pyrazine-4(1<i>H</i>)-carboxamide (TAK-915), for the Treatment of Cognitive Disorders
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説明
<p>It has been hypothesized that selective inhibition of phosphodiesterase (PDE) 2A could potentially be a novel approach to treat cognitive impairment in neuropsychiatric and neurodegenerative disorders through augmentation of cyclic nucleotide signaling pathways in brain regions associated with learning and memory. Following our earlier work, this article describes a drug design strategy for a new series of lead compounds structurally distinct from our clinical candidate 2 (TAK-915), and subsequent medicinal chemistry efforts to optimize potency, selectivity over other PDE families, and other preclinical properties including in vitro phototoxicity and in vivo rat plasma clearance. These efforts resulted in the discovery of N-((1S)-2-hydroxy-2-methyl-1-(4-(trifluoromethoxy)phenyl)propyl)-6-methyl-5-(3-methyl-1H-1,2,4-triazol-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (20), which robustly increased 3′,5′-cyclic guanosine monophosphate (cGMP) levels in the rat brain following an oral dose, and moreover, attenuated MK-801-induced episodic memory deficits in a passive avoidance task in rats. These data provide further support to the potential therapeutic utility of PDE2A inhibitors in enhancing cognitive performance.</p>
収録刊行物
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- CHEMICAL & PHARMACEUTICAL BULLETIN
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CHEMICAL & PHARMACEUTICAL BULLETIN 65 (11), 1058-1077, 2017
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
- 1390001204179107584
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- NII論文ID
- 130006191503
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- NII書誌ID
- AA00602100
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- ISSN
- 13475223
- 00092363
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- NDL書誌ID
- 028601730
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- PubMed
- 29093293
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- 本文言語コード
- en
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- 資料種別
- journal article
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- データソース種別
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- JaLC
- NDLサーチ
- Crossref
- PubMed
- CiNii Articles
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- 抄録ライセンスフラグ
- 使用不可