Preliminary Evaluation Of The Pharmacokinetics And Safety Of CDER167,A Novel Candidate Compound For Treatment Of Hyperuricemia

BackgroundHyperuricemia is a metabolic syndrome caused by the disorder of purine metabolism.In recent years,it has shown a significant increase and younger trend.It is another metabolic disease with a high prevalence after diabetes.So far,the majority of medical workers in my country have not paid enough attention to hyperuricemia,and the current situation is not optimistic.The treatment of hyperuricemia mainly includes drug therapy and non-drug therapy,both of which are an important part of the treatment of hyperuricemia.Drug treatment mainly includes xanthine oxidase inhibitors,uric acid excretion drugs and recombinant uricase preparations,however,there are not many types of drugs used clinically and many have application restrictions.ObjectiveIn this study,compound CDER167 was synthesized based on existing uric acidlowering drugs.CDER167 has inhibitory effects on URAT1 and GLUT9,and its uratelowering effect in vivo has also been proven.The purpose of this study is to conduct a preliminary evaluation of the pharmacokinetics and safety of CDER167 in vivo.Method1.Determine the plasma drug concentration of CDER167 and RDEA3170 in the plasma of SD rats by establishing an HPLC-MS/MS method,and calculate the pharmacokinetic parameters;2.Establish the human liver microsomal temperature incubation system model to determine the metabolic type of CDER167 and determine the metabolites;3.Carry out mouse acute toxicity dose exploration experiment,rat long-term toxicity dosage exploration experiment and cardiac hERG toxicity experiment,and preliminarily evaluate the safety of CDER 167.Results and conclusions1.In this study,the HPLC-MS/MS method was successfully established and verified the effectiveness of the simultaneous determination of CDER167 and RDEA3170.Studies have shown that CDER167 is rapidly absorbed,and individual differences are large.The absolute bioavailability of CDER167 is 27.17%;2.This study successfully established the incubation system of CDER167 in human liver microsomes,and initially judged the type of metabolism of CDER167.During the metabolism process,+2H(365.1-279.2),+CH2(377.1-277.2),+O(379.1293.2),+C2H4(391.1-277.2)reaction may occur.CYP3A4 enzyme is an important metabolic enzyme involved in the metabolism of CDER167;3.Acute toxicity and long-term toxicity groping test results show that a certain dose of CDER167 is toxic to animals.The toxicity symptoms are mainly manifested in the respiratory system.Rats have obvious wheezing symptoms.Anatomy can reveal abnormalities in the lungs.The test results suggest that the dose range for the formal acute toxicity test in mice should be set between 150-1500mg/kg,and the test should have 5 dose groups and 1 solvent control group;the dose range of the formal long-term toxivity test in rats should be set at 150-750mg/kg,and the test should have 3 dose groups and 1 solvent control group.Cardiac hERG toxicity test showed that 5μM CDER167 has no cardiac hERG toxicity.