Discovery and Characterization of a New Class of C5aR1 Antagonists Showing In Vivo Activity.
J Med Chem
; 67(5): 4100-4119, 2024 Mar 14.
Article
em En
| MEDLINE
| ID: mdl-38482828
ABSTRACT
C5a is an anaphylatoxin protein produced by the cleavage of the complement system's component C5 protein. It signals through the G-protein-coupled receptor C5a receptor 1 (C5aR1) to induce the chemotaxis of primarily neutrophils and monocytes and the release of inflammatory molecules. A large body of evidence linking C5aR1 signaling to acute and chronic inflammatory disorders has triggered interest in developing potent C5aR antagonists. Herein we report the discovery of new C5aR1 antagonistic chemical classes. Many representatives showed low nanomolar IC50 values in a C5aR1 ß-arrestin-2 recruitment assay, inhibiting the migration of human neutrophils toward C5a and the internalization of the receptor in human whole blood. Two leading compounds were characterized further in vivo. Target engagement of the receptor by these two C5aR1 antagonists was demonstrated in vivo. In particular, the inhibition of migration in vitro with the two compounds further translated in a dose-dependent efficacy in a rat model of C5a-induced neutrophilia.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Complemento C5a
/
Receptor da Anafilatoxina C5a
Limite:
Animals
/
Humans
Idioma:
En
Revista:
J Med Chem
Assunto da revista:
QUIMICA
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Suíça