Discovery of Clinical Candidate TAK-915, a Highly Potent, Selective, and Brain Penetrating Novel Phosphodiesterase 2A Inhibitor

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  • 高活性・高選択性・高い中枢移行性を示す新規ホスホジエステラーゼ2A阻害薬TAK-915の創薬研究
  • 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>

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