Structural development of N-(4-phenoxyphenyl)benzamide derivatives as novel SPAK inhibitors blocking WNK kinase signaling
Structural development of N-(4-phenoxyphenyl)benzamide derivatives as novel SPAK inhibitors blocking WNK kinase signaling
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DOI：
10.1016/j.bmcl.2020.127408
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发表时间：
2020-09-01
影响因子：
2.7
通讯作者：
Kagechika, Hiroyuki
中科院分区：
文献类型：
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作者：
Fujii, Shinya;Kikuchi, Eriko;Kagechika, Hiroyuki
我们在此报道了N-(4-phenoxyphenyl)苯酰胺衍生物作为新型SPAK （STE20/ sps1相关脯氨酸/富丙氨酸激酶）抑制剂的结构发展。无赖氨酸激酶（WNK）与OSR1（氧化应激反应激酶1）/SPAK和NCC （NaCl共转运体）信号级联的异常激活导致特征性的盐敏感性高血压，因此WNK-OSR1/SPAK-NCC级联抑制剂是抗高血压药物的候选药物。以先导化合物2的结构为基础，研究了N-(4-phenoxyphenyl)苯酰胺衍生物的合成孔径（SAR），并确定了化合物20l为有效的SPAK抑制剂。化合物201是一类很有前途的新型抗高血压药物。
We report here structural development of N-(4-phenoxyphenyl)benzamide derivatives as novel SPAK (STE20/ SPS1-related proline/alanine-rich kinase) inhibitors. Abnormal activation of the signal cascade of with-no-lysine kinase (WNK) with OSR1 (oxidative stress-responsive kinase 1)/SPAK and NCC (NaCl cotransporter) results in characteristic salt-sensitive hypertension, and therefore inhibitors of the WNK-OSR1/SPAK-NCC cascade are candidates for antihypertensive drugs. Based on the structure of lead compound 2, we examined the SAR of N-(4-phenoxyphenyl)benzamide derivatives, and developed compound 20l as a potent SPAK inhibitor. Compounds 20l is a promising candidate for a new class of antihypertensive drugs.