Summary of main observation and conclusion Macrocycle has attracted the attention of many researchers in the field of medicinal chemistry due to its unique advantages and good prospects,but the difficulties in drug de...Summary of main observation and conclusion Macrocycle has attracted the attention of many researchers in the field of medicinal chemistry due to its unique advantages and good prospects,but the difficulties in drug design and synthesis of macrocycle limit its applications.In this study,a series of macrocyclic derivatives designed from anaplastic lymphoma kinase(ALK)inhibitor lorlatinib were synthesized as Janus kinase 2(JAK2)selective inhibitors.Among them,17f had the best inhibitory activity(IC50=0.177μmol·L^-1)and selectivity for JAK2 over JAK1 and JAK3,which indicated that design of the macrocyclic derivatives might be a feasible strategy for the discovery of novel selective JAK2 inhihitors.展开更多
基金The research is supported in part by the National Key Research and Development Program(Grant No.2016YFA0502304)the National Natural Science Foundation of China(Grant No.81825020)+2 种基金the National Science&Technology Major Project"Key New Drug Creation and Manufacturing Program",China(No.2018ZX09711002)the Fundamental Research Funds for the Central UniversitiesHonglin Li is also sponsored by the National Program for Special Supports of Eminent Professionals and the National Program for Support of Top-Notch Young Professionals.
文摘Summary of main observation and conclusion Macrocycle has attracted the attention of many researchers in the field of medicinal chemistry due to its unique advantages and good prospects,but the difficulties in drug design and synthesis of macrocycle limit its applications.In this study,a series of macrocyclic derivatives designed from anaplastic lymphoma kinase(ALK)inhibitor lorlatinib were synthesized as Janus kinase 2(JAK2)selective inhibitors.Among them,17f had the best inhibitory activity(IC50=0.177μmol·L^-1)and selectivity for JAK2 over JAK1 and JAK3,which indicated that design of the macrocyclic derivatives might be a feasible strategy for the discovery of novel selective JAK2 inhihitors.
