Design And Synthesis Of A Novel LXR Agonist

Liver X receptors(LXRs)are members of the nuclear receptor family.They were originally reported as cholesterol regulators,so they were named because of their abundant expression in the liver.LXR was activated after binding with ligand,and combined with retinol X receptor(RXR)to form heterodimer(LXR/XRX),and then combined with LXREs in the promoter of target gene to induce the expression of target gene.LXR binds to endogenous ligands or synthetic ligands and activates them,which can induce and regulate the expression of a series of genes such as cholesterol metabolism,lipid metabolism,glucose metabolism,macrophage immune and inflammatory response,so LXR is an important target for treating human diseases.In this paper,the 1,2,4-oxadiazole derivative of LXR agonist was selected as the lead compound,and the LXR agonist was reported in the reference part.The target compound was designed by using the principle of bioelectronic isotropy and structural substitution technology,and the oxadiazole ring of the lead compound was changed into thiazole ring,and the side chain was selected from the structural side chain of LXR agonist known in the reference part.Fourteen novel LXR agonists WLL-A1-WLL-A7 and WLL-B1-WLL-B7 were designed.WLL-A1 and WLL-B1 are selected as representatives to connect with LXR crystal by computer-aided design software,and the results show that they can be well combined.In this paper,the synthesis route of 1,2,4-oxadiazole derivatives was improved,and the total yield reached 14.33%.Referring to the synthesis route of lead compounds,four synthesis routes of LXR agonists were determined by simulation analogy and inverse synthesis analysis: starting from 4-fluoro-3(trifluoromethyl)benzonitrile,thiazole ring intermediates were generated by sulfation reaction and cyclization reaction,and LXR agonists were obtained by substitution reaction,deprotection reaction,reductive amination reaction,oxidation reaction and sulfoximine reaction.