Design,synthesis,and Structure-activity-relationship Of Small Molecule CXCR4 Antagonists Of Aminoprimidines

The chemokine receptor CXCR4 is a highly conserved seven-pass transmembrane G protein-coupled receptor.Because CXCR4 is closely related to the occurrence of various diseases such as HIV entry and tumor metastasis,drug development with its target has become a research hotspot.AMD3100 is currently the only CXCR4 small molecule inhibitor marketed for hematopoietic stem cell transplantation in patients with non-Hodgkin's lymphoma and multiple myeloma.However,due to the strong side effects of AMD3100 and poor oral bioavailability,it can only be administered in a short-term clinical dose.Therefore,the development of safe and oral small molecule CXCR4 inhibitors is particularly urgent.Previously,based on the reported CXCR4 small molecule inhibitor AMD070,our group obtained a series of structural optimizations to obtain compounds 6 with good activity and physicochemical properties.However,compound 6 exhibited a shorter half-life in the investigation of liver microsome stability in vitro,indicating that the in vitro metabolic stability of compound 6 was poor.Therefore,the main purpose of this project is to continue to optimize on the basis of compound 6,in order to obtain a novel oral small molecule CXCR4 inhibitor with novel structure,good metabolic stability in vitro,and good activity.First,we modify the tetrahydroquinoline ring in the structure of the compound 6 with an oxygen atom or a cyclopropyl group to obtain a series of compounds represented by the compounds 7,11.Although they retained good activity,the in vitro metabolic stability did not improve significantly.Next,we opened the tetrahydroquinoline ring of compound 6 and then cyclized with the central nitrogen atom to obtain a series of compounds which retain activity.Among them,the compound 26 performed excellently.It not only showed good activity in binding experiments,calcium flux regulation experiments and CXCL12 induced cell traction experiments,but also showed good results in experiments on liver microsome stability in vitro.In addition,in vivo metabolism experiments on compound 26 are also being carried out gradually,and it is hoped that a new approach for the early marketing of oral small molecule CXCR4 inhibitors can be provided.