Design,synthesis And Activity Of Aromatic Heterocyclic RIPK1 Small Molecule Inhibitors And Synthesis And Structure Optimization Of Smo Protein Inhibitors

This paper is divided into two parts:Part ?:In recent years,necroptosis has been recognized as a controllable way of cell death,and it is associated with a variety of inflammatory diseases.Among multiple potential therapeutic targets to mitigate necroptosis related diseases,RIPK1 has emerged as the most promising one.A number of RIPK1 inhibitors have been developed by GlaxoSmithKline,among them,GSK'481 and GSK'772 displayed significant species difference between rodents and human,which limits their potential to be tested in preclinical disease models.In our previous work,more than 1000 compounds were screened.Compound PK6 was identified as a potent inhibitor for necroptosis.Optimization based on PK6 led to compound A2.In this study,A2 was used as the lead compound,17 compounds with new molecular structures were designed and synthesized.Among them,A15 not only had improved inhibitory activity against necroptosis(EC50=5.3 nM),but also had good competitive binding activity to RIPK1 protein,and its Kd value reached 12 nM.However,its performance in liver microsomal metabolic stability experiments is not good enough(HLM:t1/2=16.38 min),and it still needs further optimization and modification in order to obtain ideal new small molecular RIPK1 inhibitors.Part ?:Hedgehog pathway plays an important role in embryonic development.Over activation of hedgehog signaling in adults is involved in cancer.Smo receptor is an important part of Hedgehog pathway,which has become an attractive target for the treatment of human cancers.Vismodegib and Sonidegib are FDA approved Smo inhibitors,but some patients have developed resistance to Vismodegib and Sonidegib.Therefore,it is still necessary to explore Smo inhibitors with new skeletons to enhance anti-tumor efficacy and solve the problem of drug resistance.In the preliminary work,racemic compound 23 with good activity was obtained by structure optimization(IC50=7.1 nM).The enantiomeric isomer of 23,compound 25,was synthesized and displayed potent inhibitory activity in the drug resistance D473H mutant.However,the performance of 25 in liver microsomal metabolic stability test was not ideal(HLM:Clint=2700 mL/min/kg).In this thesis,compound 23 and compound 24 were used as lead compounds to optimize the structure of group 2-methylcyclohexylamine,in order to eliminate chirality and avoid the influence of potential metabolic sites.A total of 10 compounds are designed and synthesized.We will carry out BODIPY-cyclopamine competitive test and liver microsomal metabolic stability test on the compounds with good activity to obtain ideal Smo protein inhibitors.