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- 味上 達
- 武田薬品工業株式会社
書誌事項
- タイトル別名
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- Discovery of Clinical Candidate TAK-915, a Highly Potent, Selective, and Brain Penetrating Novel Phosphodiesterase 2A Inhibitor
- コウカッセイ ・ コウセンタクセイ ・ タカイ チュウスウ イコウセイ オ シメス シンキ ホスホジエステラーゼ 2A ソガイヤク TAK-915 ノ ソウヤク ケンキュウ
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<p>Phosphodiesterase (PDE) 2A inhibitors have emerged as a novel mechanism with potential therapeutic option to ameliorate cognitive dysfunction in schizophrenia or Alzheimer’s disease through upregulation of cyclic nucleotides in the brain and thereby achieve potentiation of cyclic nucleotide signaling pathways. In the search for a potent, selective, in vivo active PDE2A inhibitor, pyrazolo[1,5-a]pyrimidine 2 was identified as a hit compound from high-throughput screening (HTS) campaign of our in-house compound library. The ligand-based lead generation efforts led to the discovery of the promising lead molecule 8a. Further optimization of this lead was guided by its X-ray co-crystal structure in complex with PDE2A, thus culminating in the identification of the clinical candidate (1, TAK-915), which demonstrates an appropriate combination of potency, PDE selectivity, and favorable pharmacokinetic (PK) properties, including brain penetration. This article details the expedited lead generation and ensuing optimization approaches leading to the discovery of clinical candidate, as well as the synthetic route of TAK-915 for 1-week toxicological studies.</p>
収録刊行物
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- 有機合成化学協会誌
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有機合成化学協会誌 79 (6), 581-591, 2021-06-01
公益社団法人 有機合成化学協会
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詳細情報 詳細情報について
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- CRID
- 1390569789595928064
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- NII論文ID
- 130008049976
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- NII書誌ID
- AN0024521X
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- ISSN
- 18836526
- 00379980
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- NDL書誌ID
- 031568165
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- 本文言語コード
- ja
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- データソース種別
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- JaLC
- NDL
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- CiNii Articles
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