Design、Synthesis And Optimization Of RIP1 Kinase Inhibitors That Inhibit Necroptosis

Cell necrosis has been considered an accidental,uncontrolled cell death in the past.But recent studies have illustrated that necrosis could be mediated by a series of controlled signal transduction pathways and execution mechanisms,also known as necroptosis.Necroptosis is indicated in ischemic brain/kidney injury,atherosclerosis,myocardial infarction,pancreatitis,systemic inflammatory response syndrome,therefore,inhibition of necroptosis may provide new opportunities for the treatment of these diseases.At present,several molecular targets with potential therapeutic application have been reported,including RIP1,RIP3 and MLKL.Small molecule inhibitors targeting each of the above target have been reported,with those targeting RIP1 kinase have advanced most rapidly.GSK’481 is a potent RIP1 kinase inhibitor with high kinase selectivity which was published by GSK.GSK2982772 is a small molecule inhibitor that is optimized from GSK’481 and it is now in phase Ⅱ clinical trials.However,GSK’481 series demonstrated paramount species selectivity for inhibition of primate RIP1 compared to nonprimate RIP1,hampering efficacy evaluation in preclinical animal experiments.In order to solve the problem of the species selectivity in GSK series,we designed and synthesized a series of compounds with new skeleton,named as α series,according to the SAR described in the published literatures.However,the activity of the 15 new compounds was lower than that of GSK’481,did not achieve the desire results.Subsequently,we screened more than 1000 compounds synthesized by our research group and discovered β1 series as necroptosis inhibitors.Afterwards,21 new compounds,called β compounds(β1-β18、β20、β21),were synthesized by optimizing the structure of the hit compounds β1.Among them,β1、β16、β18、β19 had anti-necroptosis activity close to that of Nec-1 in HT29 cell line.Moreover,β1 and β8 had both presented potent and similar inhibition activity to necroptosis in HT29 cell lines and L929 cell lines,indicating that there is no significant species selectivity in these compounds.This manifested that these new compounds are qualified to further structural optimization and pharmacokinetic study.The test working on inhibitory activity of RIP1 kinase is in progress.