Discovery of novel biaryl benzoxazepinones as dual-mode receptor-interacting protein kinase-1 (RIPK1) inhibitors.
Bioorg Med Chem
; 100: 117611, 2024 Feb 15.
Article
em En
| MEDLINE
| ID: mdl-38309200
ABSTRACT
Systemic inflammatory response syndrome (SIRS), an exaggerated defense response of the organism to a noxious stressor, involves a massive inflammatory cascade that ultimately leads to reversible or irreversible end-organ dysfunction and even death. Suppressing RIPK1, a key protein in necroptosis pathway, has been proven to be an effective therapeutic strategy for inflammation and SIRS. In this study, a series of novel biaryl benzoxazepinone RIPK1 inhibitors were designed and synthesized by introducing different aryl substituents at the C7 position of benzoxazepinone. As a result, p-cyanophenyl substituted analog 19 exhibited the most potent in vitro anti-necroptotic effect in HT-29 cells (EC50 = 1.7 nM) and superior protection against temperature loss and death in mice in the TZ-induced SIRS model compared to GSK'772. What's more, in vivo analysis of the levels of inflammatory factors in mice also revealed that compound 19 had better anti-inflammatory activity than GSK'772.
Palavras-chave
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Síndrome de Resposta Inflamatória Sistêmica
/
Proteína Serina-Treonina Quinases de Interação com Receptores
/
Inflamação
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Bioorg Med Chem
Assunto da revista:
BIOQUIMICA
/
QUIMICA
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
China