Structural Development of Salicylanilide‐Based SPAK Inhibitors as Candidate Antihypertensive Agents
Structural Development of Salicylanilide‐Based SPAK Inhibitors as Candidate Antihypertensive Agents
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DOI：
10.1002/cmdc.202100273
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发表时间：
2021-06
期刊：
影响因子：
3.4
通讯作者：
S. Fujii;Eriko Kikuchi;Honoka Suzuyama;Y. Watanabe;Mari Ishigami‐Yuasa;H. Masuno;Takayasu Mori;Kiyoshi Isobe;S. Uchida;H. Kagechika
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作者：
S. Fujii;Eriko Kikuchi;Honoka Suzuyama;Y. Watanabe;Mari Ishigami‐Yuasa;H. Masuno;Takayasu Mori;Kiyoshi Isobe;S. Uchida;H. Kagechika
高血压是药物发现的重要靶点。我们专注于无赖氨酸激酶（WNK）-氧化应激反应1（OSR 1）和STE 20/SPS 1相关的富含脯氨酸-丙氨酸蛋白激酶（SPAK）-NaCl协同转运蛋白（NCC）信号级联作为潜在靶点，我们之前开发了WNK-OSR 1/SPAK-NCC信号抑制剂的筛选系统。在此，我们使用该系统来检查作为SPAK激酶抑制剂的水杨酰苯胺衍生物的结构活性关系（SAR）。基于我们先前的热门化合物芳氧基苯甲酰苯胺衍生物2和兽用驱虫剂氯氰碘柳胺（3）的结构设计和开发导致发现化合物10 a作为具有降低的毒性的有效SPAK抑制剂。化合物10 a在体内可降低小鼠肾脏中NCC的磷酸化水平，并且似乎是一类新的抗高血压药物的有希望的先导化合物。
Hypertension is an important target for drug discovery. We have focused on the with‐no‐lysine kinase (WNK)‐oxidative stress‐responsive 1 (OSR1) and STE20/SPS1‐related proline‐alanine‐rich protein kinase (SPAK)‐NaCl cotransporter (NCC) signal cascade as a potential target, and we previously developed a screening system for inhibitors of WNK‐OSR1/SPAK‐NCC signaling. Herein we used this system to examine the structure‐activity relationship (SAR) of salicylanilide derivatives as SPAK kinase inhibitors. Structural design and development based on our previous hit compound, aryloxybenzanilide derivative 2, and the veterinary anthelmintic closantel (3) led to the discovery of compound 10 a as a potent SPAK inhibitor with reduced toxicity. Compound 10 a decreased the phosphorylation level of NCC in mouse kidney in vivo, and appears to be a promising lead compound for a new class of antihypertensive drugs.