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
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.
References
1) Ren?et al.?(2017),?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. Med. Chem.?60?972
