RIPA-56

Description

RIPA-56 (1956370-21-0) is a potent (IC50= 13 nM, EC50= 28nM for HT-29 cells) and selective inhibitor of Receptor-Interacting Protein 1 (RIP1) kinase with significant metabolic stability (t1/2= 128min human liver microsomal stability assay). RIPA-56 showed excellent kinase selectivity and did not inhibit IDO at 200 μM.It was able to block the progression of multiple sclerosis in an immune-induced demyelination model.2

Uses

RIPA-56 is a highly potent, selective, and metabolically stable inhibitor of receptor-interacting protein 1 (RIP1) with an IC50 of 13 nM. RIPA-56 can be used for the treatment of systemic inflammatory response syndrome[1].

Biochem/physiol Actions

RIPA-56 is a metabolically stable type III kinase inhibitor that targets receptor-interacting protein 1 kinase (RIP1; RIPK1) in a highly potent and selective manner (RIP1 IC50 = 13 nM) by locking RIP1 in its inactive form, exhibiting no inhibitory potency toward RIP3, IDO or a panel of multiple kinases (tested at 10, 200, and 5 μM, respectively). RIPA-56 protects against TNFα-induced necroptosis (necrosis) upon apoptosis/NF-κB pathway blockage (EC50= 27 nM/murine L929 and 28 nM/human HT-29 cells) in cultures as well as TNFα-induced mortality and multiorgan damage in a murine model of systemic inflammatory response syndrome (SIRS) in vivo (100% survival rate with 3 mg/kg/12 h or single 6 mg/kg i.p.) with good pharmacokinetics and bioavailability (F post 10 mg/kg p.o. or i.p. dosing = 22% and 100%, respectively, of 2 mg/kg i.v.). Long-term daily RIPA-56 supplementation (150 or 300 mg/kg in chow) is reported to prevent aging-associated deterioration of the male reproductive system in mice.

in vivo

storage

Store at -20°C

Background

RIPA-56 is a potent, selective, and metabolically stable inhibitor of receptor-interacting protein 1 kinase with an IC50 value of 13 nM, with no effect on RIP3 kinase activity at a 10 μM concentration. RIPA-56 has been shown to reduce TNFα-induced mortality and multiorgan damage in systemic inflammatory response syndrome. Blocking the activity of RIP1 kinase allows for cell survival and proliferation in the presence of death receptor ligands. In vivo studies have also shown that necroptosis can be inhibited in the testes of busulfan-induced mice by the suppression of RIP1 kinase with RIPA-56. This small molecule can protect myelin structures by blocking the demyelination and inflammation of spinal cord white matter in mice experimental autoimmune encephalomyelitis-induced models, halting the progression of multiple sclerosis.

References

[1] YAN REN. Discovery of a Highly Potent, Selective, and Metabolically Stable Inhibitor of Receptor-Interacting Protein 1 (RIP1) for the Treatment of Systemic Inflammatory Response Syndrome[J]. Journal of Medicinal Chemistry, 2016, 60 3: 972-986. DOI:10.1021/acs.jmedchem.6b01196