RI-962 is a potent and selective inhibitor of RIPK1 that dose-dependently protects cells from necrotic apoptosis induced by TNFα, Smac mimics, and Z-VAD-FMK by inhibiting RIPK1, RIPK3, and MLKL phosphorylation with EC50=10.0 nM~17.8 nM, and improves survival in mice in two models of inflammation.

RI-962 exhibits a strong inhibitory activity against RIPK1, demonstrated by an IC50 of 35.0 nM [1]. Furthermore, RI-962 offers a protective effect against necroptotic cell death, with EC50 values of 10.0 nM for HT29 cells, 4.2 nM for L929 cells, 11.4 nM for J774A.1 cells, and 17.8 nM for U937 cells [1]. At concentrations ranging from 0-100 μM over 24 hours, RI-962 safeguards cells from TSZ-induced necroptosis by impeding RIPK1's kinase activity [1].

RI-962, administered intraperitoneally (i.p.) at a dosage of 40 mg/kg once daily for 10 days, alleviates TNFα-induced systemic inflammatory response syndrome (SIRS) and mitigates inflammation in acute DSS-induced colitis [1]. The pharmacokinetic profile of RI-962 in rats, following intravenous (i.v.), intraperitoneal (i.p.), and oral (p.o.) administration at doses of 5 and 20 mg/kg, includes a half-life (T1/2) of 2.1±0.2 hours (i.v., 5 mg/kg), 1.3±0.2 hours (p.o., 20 mg/kg), and 8.5±1.6 hours (i.p., 20 mg/kg). The peak plasma concentration (Cmax) reached 12170.4±1198.5 ng/mL (i.v.), 674.2±424.7 ng/mL (p.o.), and 3603.3±693.3 ng/mL (i.p.). The area under the concentration-time curve from zero to the last observed time point (AUC 0–t) and to infinity (AUC 0–∞) showed comparable values. The volume of distribution at steady-state (Vss) was recorded for i.v. administration at 0.4±0.1 L/kg, and the mean residence time (MRT 0–∞) varied across administration routes [1].