Design, synthesis, and structure-activity relationship of novel RIPK2 inhibitors.
Bioorg Med Chem Lett
; 75: 128968, 2022 11 01.
Article
em En
| MEDLINE
| ID: mdl-36058467
ABSTRACT
The NOD1/2 (nucleotide-binding oligomerization domain-containing protein 1/2) signaling pathways are involved in innate immune control and host defense. NOD dysfunction can result in a variety of autoimmune disorders. NOD-induced generation of inflammatory cytokines is mediated by receptor-interacting protein kinase 2 (RIPK2), which has been considered as a promising therapeutic target. Herein, we disclose the design, synthesis, and SAR study of a series of RIPK2 inhibitors. The lead compound 17 displayed a high affinity for RIPK2 (Kd = 5.9 nM) and was capable of inhibiting RIPK2 kinase function in an ADP-Glo assay. In vitro DMPK studies showed that compound 17 had good metabolic stability and no CYP inhibition. Compound 17 effectively suppressed inflammatory cytokine production in both cells and animal model.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Iohexol
/
Citocinas
Limite:
Animals
Idioma:
En
Revista:
Bioorg Med Chem Lett
Assunto da revista:
BIOQUIMICA
/
QUIMICA
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
China