Discovery and Synthetic Study of Balipodect, a Novel Phosphodiesterase 10A Inhibitor
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- Yoshikawa Masato
- Takeda Pharmaceutical Company Limited
Bibliographic Information
- Other Title
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- 新規ホスホジエステラーゼ10A阻害薬バリポデクトの創製および合成法開発
- シンキ ホスホジエステラーゼ 10A ソガイヤク バリポデクト ノ ソウセイ オヨビ ゴウセイホウ カイハツ
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Abstract
<p>Phosphodiesterase 10A (PDE10A) inhibitors are expected as a novel treatment of schizophrenia with no or less adverse effects caused by typical and atypical antipsychotic drugs. In the pursue of developing a novel PDE10A inhibitor, a pyridazin-4(1H)-one derivative was identified as a hit compound by high throughput screening (HTS) and the X-ray co-crystal structure of the hit compound with PDE10A enabled us a rational structure-based drug design (SBDD) approach. Following optimization focusing on topological polar surface area (TPSA) to enhance the brain-penetration led to discovery of Balipodect, a highly potent, selective, and orally active PDE10A inhibitor (IC50=0.30 nM, 18,000-fold selectivity over other PDEs). Balipodect is being developed in clinical trials for the treatment of schizophrenia. This article describes the successful example of the structure- and property-based drug designs from the HTS hit to the clinical compound. The development of optimal synthetic routes depending on each stage of the drug discovery is also discussed.</p>
Journal
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- Journal of Synthetic Organic Chemistry, Japan
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Journal of Synthetic Organic Chemistry, Japan 79 (6), 570-580, 2021-06-01
The Society of Synthetic Organic Chemistry, Japan
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Keywords
Details 詳細情報について
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- CRID
- 1390288314620292096
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- NII Article ID
- 130008049979
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- NII Book ID
- AN0024521X
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- ISSN
- 18836526
- 00379980
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- NDL BIB ID
- 031568120
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- Text Lang
- ja
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- Data Source
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- JaLC
- NDL
- Crossref
- CiNii Articles
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- Abstract License Flag
- Disallowed