Bioorganic and medicinal chemistry letters (2020)
Update date:2022-08-03
Topics:
Fujii, Shinya
Ishigami-Yuasa, Mari
Isobe, Kiyoshi
Kagechika, Hiroyuki
Kikuchi, Eriko
Mori, Takayasu
Suzuyama, Honoka
Uchida, Shinichi
Watanabe, Yuko
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.
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