Structural Development of Salicylanilide-Based SPAK Inhibitors as Candidate Antihypertensive Agents
| Autor: | Eriko Kikuchi, Hiroyuki Masuno, Takayasu Mori, Yuko Watanabe, Shinichi Uchida, Hiroyuki Kagechika, Kiyoshi Isobe, Honoka Suzuyama, Shinya Fujii, Mari Ishigami-Yuasa |
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| Rok vydání: | 2021 |
| Předmět: |
Cell Survival
Pharmacology Protein Serine-Threonine Kinases Biochemistry Salicylanilides chemistry.chemical_compound Mice Structure-Activity Relationship Drug Development In vivo Drug Discovery Animals General Pharmacology Toxicology and Pharmaceutics Protein kinase A Protein Kinase Inhibitors Antihypertensive Agents Cells Cultured Dose-Response Relationship Drug Molecular Structure urogenital system Drug discovery Chemistry Kinase Organic Chemistry Salicylanilide Molecular Medicine Phosphorylation Cotransporter Lead compound |
| Zdroj: | ChemMedChem. 16(18) |
| ISSN: | 1860-7187 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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