Structural Development of Salicylanilide-Based SPAK Inhibitors as Candidate Antihypertensive Agents.
ChemMedChem
; 16(18): 2817-2822, 2021 09 16.
Article
em En
| MEDLINE
| ID: mdl-34109743
ABSTRACT
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 inâ
vivo, and appears to be a promising lead compound for a new class of antihypertensive drugs.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Salicilanilidas
/
Proteínas Serina-Treonina Quinases
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Inibidores de Proteínas Quinases
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Desenvolvimento de Medicamentos
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Anti-Hipertensivos
Limite:
Animals
Idioma:
En
Revista:
ChemMedChem
Ano de publicação:
2021
Tipo de documento:
Article