RIPK1-IN-11

RIPK1-IN-11 is a potent and orally active RIPK1 inhibitor (Kd=9.2 nM; IC50=67 nM). RIPK1-IN-11 inhibits necroptosis in both human and mouse cells (EC50=17-30 nM). Anti-inflammatory activity[1].

Signaling Pathways >> Apoptosis >> RIP kinase

Research Areas >> Inflammation/Immunology

RIPK1-IN-11 (compound 70) (24 hours; for 1h prior to the treatment of TNFα) efficiently blocks necroptosis induced by TNFα in both human and mouse cells (EC50=17-30 nM)[1]. Pharmacokinetic profiles of compound 70 in male SD rats IV (2 mg/kg) PO (10 mg/kg) Tmax (h) 1.2 Cmax (ng/mL) 1330 1241 AUC0-24 (ng/mL∗h) 1208 3827 t1/2 (ng/mL) 1.0 1.7 CL (mL/min/kg) 33 Vd, ss (L/kg) 2.4 F (%) 63%

RIPK1-IN-11 (3 mg/kg; i.p. for 30 min, followed by injection with TNFα) blocks hypothermia and death in mice in the TNFα-induced SIRS model[1]. RIPK1-IN-11 (5 mg/kg, 25 mg/kg; p.o.; 7 days; C57BL/6 mouse) exhibits no obvious toxicity in mice[1]. Animal Model: C57BL/6 female mice (TNF-induced systemic inflammatory response syndrome)[1] Dosage: 3 mg/kg Administration: i.p. for 30 min, followed by injection with TNFα (0.25 μg/g) Result: Significantly reduced TNFα-induced temperature loss and ameliorated lethal shock in mice.

[1]. Li Z, Hao Y, Yang C, et al. Design, synthesis, and evaluation of potent RIPK1 inhibitors with in vivo anti-inflammatory activity. Eur J Med Chem. 2022;228:114036.