Design,synthesis And Biological Evaluation Of Novel GPR183 Antagonist

GPR183,also known as EBI2,is a member of the rhodopsin-like subfamily of class A G protein-coupled receptors.GPR183 was first discovered in 1993 due to its high expression in Epstein-Barr virus infected cells.Oxysterol,7,25-OHC is the endogenous ligand of GPR183.Recent studies have shown that oxysterols and metabolically related cholesterol hydroxylase play an important role in the pathogenesis of osteoarthritis(OA).It suggests that GPR183 may be directly involved in the development of osteoarthritis and the study on the bioactivity of GPR183 small molecule antagonist may provide a new direction for the treatment of OA.There are only two series of GPR183 small molecule antagonists reported,GSK682753A and NIBR189.Although NIBR189 has good antagonistic activity,the conjugated carbonyl structure may covalently bond with protein amino acid residues,resulting in potential off-target effects and toxic side effects.We modified the structure of NIBR189 at three positions and obtained series novel pyridine piperazine compounds with good activity data in the calcium flow assay on the basis of NIBR189.The structure modification results of intermediate parent nuclei showed that pyridine was the best,and the number and position of nitrogen atoms had a crucial effect on the activity.The results of Linker region showed that carbonyl and sulfonyl linked compounds 1A and 1D had better activity.The results of the structure modification of R~1 substituents showed that R~1had little effect on the activity and compound 1I had the best activity.In addition,we explored the biological function of compound 4C.The results showed that compound4C can promote chondrocyte differentiation and inhibit the expression of MMP-13and MMP-3.In conclusion,we have obtained a new type of GPR183 small molecule antagonists with novel structure,which showed great potential in the cell membrane types related to osteoarthritis and provide new ideas for the treatment of osteoarthritis.