Discovery of a Highly Potent, Selective, and Metabolically Stable Inhibitor of Receptor-Interacting Protein 1 (RIP1) for the Treatment of Systemic Inflammatory Response Syndrome

On the basis of its
essential role in driving inflammation and
disease pathology, cell necrosis has gradually been verified as a
promising therapeutic target for treating atherosclerosis, systemic
inflammatory response syndrome (SIRS), and ischemia injury, among
other diseases. Most necrosis inhibitors targeting receptor-interacting
protein 1 (RIP1) still require further optimization because of weak
potency or poor metabolic stability. We conducted a phenotypic screen
and identified a micromolar hit with novel amide structure. Medicinal
chemistry efforts yielded a highly potent, selective, and metabolically
stable drug candidate, compound 56 (RIPA-56). Biochemical studies and molecular docking revealed that RIP1
is the direct target of this new series of type III kinase inhibitors.
In the SIRS mice disease model, 56 efficiently reduced
tumor necrosis factor alpha (TNFα)-induced mortality and multiorgan
damage. Compared to known RIP1 inhibitors, 56 is potent
in both human and murine cells, is much more stable in vivo, and is
efficacious in animal model studies.