Discovery and optimization of 3-(indolin-5-yloxy)pyridin-2-amine derivatives as potent necroptosis inhibitors.
Arch Pharm (Weinheim)
; 357(10): e2400302, 2024 Oct.
Article
en En
| MEDLINE
| ID: mdl-38955770
ABSTRACT
Necroptosis is a form of regulated necrotic cell death and has been confirmed to play pivotal roles in the pathogenesis of multiple autoimmune diseases such as rheumatoid arthritis (RA) and psoriasis. The development of necroptosis inhibitors may offer a promising therapeutic strategy for the treatment of these autoimmune diseases. Herein, starting from the in-house hit compound 1, we systematically performed structural optimization to discover potent necroptosis inhibitors with good pharmacokinetic profiles. The resulting compound 33 was a potent necroptosis inhibitor for both human I2.1 cells (IC50 < 0.2 nM) and murine Hepa1-6 cells (IC50 < 5 nM). Further target identification revealed that compound 33 was an inhibitor of receptor interacting protein kinase 1 (RIPK1) with favorable selectivity. In addition, compound 33 also exhibited favorable pharmacokinetic profiles (T1/2 = 1.32 h, AUC = 1157 ng·h/mL) in Sprague-Dawley rats. Molecular docking and molecular dynamics simulations confirmed that compound 33 could bind to RIPK1 with high affinity. In silico ADMET analysis demonstrated that compound 33 possesses good drug-likeness profiles. Collectively, compound 33 is a promising candidate for antinecroptotic drug discovery.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Ratas Sprague-Dawley
/
Proteína Serina-Treonina Quinasas de Interacción con Receptores
/
Descubrimiento de Drogas
/
Simulación del Acoplamiento Molecular
/
Necroptosis
Límite:
Animals
/
Humans
/
Male
Idioma:
En
Revista:
Arch Pharm (Weinheim)
Año:
2024
Tipo del documento:
Article
País de afiliación:
China