Discovery of Clinical Candidate 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): A Highly Potent, Selective, and Brain -Penetrating Phosphodiesterase 2A Inhibitor for the Treatment of Cognitive Disorders
Discovery of Clinical Candidate 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): A Highly Potent, Selective, and Brain -Penetrating Phosphodiesterase 2A Inhibitor for the Treatment of Cognitive Disorders
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DOI：
10.1021/acs.jmedchem.7b00807
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发表时间：
2017-09-28
影响因子：
7.3
通讯作者：
Taniguchi, Takahiko
中科院分区：
文献类型：
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作者：
Mikami, Satoshi;Nakamura, Shinji;Taniguchi, Takahiko
磷酸二酯酶（PDE）2A抑制剂已经成为一种新的机制，具有潜在的治疗选择，通过上调脑中的环核苷酸来改善精神分裂症或阿尔茨海默病中的认知功能障碍，从而实现环核苷酸信号传导途径的增强。这篇文章详细介绍了我们最近公开的吡唑并[1，5-a]嘧啶先导化合物4 b的加速优化，从而发现了临床候选物36（TAK-915），该化合物表现出了效价、PDE选择性和有利的药代动力学（PK）特性（包括脑渗透）的适当组合。通过应用基于结构的药物设计（SBDD）来进一步提高效力和PDE选择性，再加上专注于物理化学性质的前瞻性设计来实现36的成功鉴定，以提供脑渗透。36的口服给药证明小鼠脑中3 '，5'-环鸟苷一磷酸（cGMP）水平的显著升高和大鼠在新的物体识别任务中的认知表现的改善。因此，化合物36进入了人体临床试验。
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. This article details the expedited optimization of our recently disclosed pyrazolo[1,5-a]pyrimidine lead compound 4b, leading to the discovery of clinical candidate 36 (TAK-915), which demonstrates an appropriate combination of potency, PDE selectivity, and favorable pharmacokinetic (PK) properties, including brain penetration. Successful identification of 36 was realized through application of structure-based drug design (SBDD) to further improve potency and PDE selectivity, coupled with prospective design focused on physicochemical properties to deliver brain penetration. Oral administration of 36 demonstrated significant elevation of 3',5'-cyclic guanosine monophosphate (cGMP) levels in mouse brains and improved cognitive performance in a novel object recognition task in rats. Consequently, compound 36 was advanced into human clinical trials.