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Structural Development of Salicylanilide‐Based SPAK Inhibitors as Candidate Antihypertensive Agents
Author(s) -
Fujii Shinya,
Kikuchi Eriko,
Suzuyama Honoka,
Watanabe Yuko,
IshigamiYuasa Mari,
Masuno Hiroyuki,
Mori Takayasu,
Isobe Kiyoshi,
Uchida Shinichi,
Kagechika Hiroyuki
Publication year - 2021
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202100273
Subject(s) - pharmacology , chemistry , kinase , in vivo , drug discovery , biochemistry , medicine , biology , microbiology and biotechnology
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.