The Study Of Screening Drugs For Treating Diabetic Kidney Disease Targeted Farnesol X Receptor And Its Efficacy

Diabetic kidney disease?DKD?is a chronic kidney disease caused by diabetes and one of the most serious microvascular complications of diabetes.A large number of people die every year due to DKD.However,the only treatment for DKD is to reduce urinary albumin through drugs including ACEI and ARB currently.The biggest problem in the clinical treatment of DKD is the lack of effective drugs to improve the composite of a doubling of the serum creatinine level,end-stage kidney disease,or death from renal or cardiovascular causes.So far,lots of researchers have tried to find drugs that effectively treat DKD targeted sodium-glucose cotransporter 2?SGLT2?,mineralocorticoid receptor?MR?,and farnesol X receptor?FXR?.Unfortunately,no drugs have been approved for listing at present.In order to get a novel FXR modulator for the treatment of DKD,we evaluate the effectiveness of compounds synthesized based on GS-9674 in vitro and in vivo.Firstly,thirty-nine novel compounds were synthesized based on the chemical structure of positive compound GS-9674 and then FXR agonist activity was tested by time-resolved fluorescence resonance energy transfer?TR-FRET?assay and a cell-based agonist assay.DJH002 was determined to have the best biological activity among all compounds and its activity was better than GS-9674.In addition,there was no activation of other nuclear receptors by DJH002 using a cell-based agonist assay.In order to research the preclinical pharmacokinetics of DJH002,we carried out pharmacokinetic studies on SD rats and beagle dogs,rats'tissue distribution study and the stability test in liver microsomes in vitro.After oral administration,DJH002 was found to have short half-life and low AUC from 0 to the last time point(AUC_0-t).DJH002 distributed in the gastrointestinal tract,liver,and renal but brain following oral administration in SD rats.In addition,DJH002 was stable in liver microsomes of human,dogs,rats and mice.Finally,the ZDF rats DKD model and the STAM model were used to investigate the effect of DJH002.The results showed that DJH002 can improve DKD by reducing the urinary albumin/creatinine ratio?ACR?and glomerular sclerosis index?GSI?in ZDF rats model and reducing GSI in C57 mice model.The effective dose of DJH002 is 0.1 mg/kg in ZDF rats and 0.3 mg/kg in C57 mice.As a consequence,DJH002 screened in this study is a highly effective FXR agonist that has good efficacy on DKD both in vivo and in vitro,laying a foundation for its clinical research and application.