| AZ {(E)-4-[ 2-(4-chlorophenoxy)-2-methylpropanoyloxy ]-3-methoxyphenyl acrylic acid} is a new compound that we get after the structural transformation,it is prepared by the step of acylation between chlorophenoxyacetic acid and ferulic acid which is traditional Chinese medicine active products.Study pharmacodynamics of AZ have proved that AZ has a significant treatment effect on combined hyperlipidemia in rats,the serum TC?TG and LDL-C was significantly decreased.In pharmacodynamics study we have used fenofibrate as psitive control.The experimental results show that the lowering serum TC?TG and LDL-C level was no significant difference between all AZ groups and fenofibrate group.AZ also could inhibit thrombosis formation effectively,the effect of inhibition was no significant difference between AZ and Positive control drug-aspirin.Therefore,AZ is a drug that could hypolipemic and effective antithrombotic,it can be used for the prevention and treatment of hyperlipidemia and cerebral thrombosisThis project is supported by Science and Technology Projects of Major Strategic Products of Jiangxi in 2008 funded projects.The research include the studies on the mechanism of AZ drug action,reveal the AZ hypolipidemic effect mechanism,and Synthesis and pharmacodynamic of it's derivant,observed the lipid-lowering effects of these compounds after structural transformation.Those can be provide a reference for clinical studies.Specific studies include the following aspects:1.To explore effects of AZ on hyperlipidemia in rats and the correlated modulating blood lipids mechanism.Rats were fed withhigh-cholesterol diets for 4 weeks to set up the model of hyperlipidemia rat.Starting from the fifth weeks,in addition to the normal control group and hyperlipidemia model group,the rest were ig given with AZ80,160 and 320 mg·kg-1,Fenofibrate 100 mg·kg-1or chlorophenoxy isobutyrate44 mg·kg-1+ ferulic acid 40 mg·kg-1in accordance with the grouping,once a day for 3 weeks,continued feeding with high-cholesterol diets.Detect different kinds of serum indicators by blooding in orbital venous plexus.Compared with the hyperlipidemia model group,AZ80,160 and 320 mg·kg-1and Fenofibrate groups can significantly reduce the levels of TC,TG and LDL-C in hypercholesterolemic rats serum,The decreasing cholesterol mechanism should include:(1)scaveng free radical,increase antioxidant activity,thereby enhance the activity of serum lipoprotein lipase(LPL)and hepatic lipase(HL),decrease TC,TG and LDL-C indirectly.(2)The accelerated hydrolysis and transfer of triglycerides and cholesterol,effectively lowering blood lipids.(3)by regulating apolipoprotein as ligands and corresponding receptors involved in lipoprotein metabolism,prompting the body fat metabolism become normal.2.The Synthesis of AZ derivant.Modify the structure of the lead compound AZ,shape esters with fatty alcohols,aromatic alcohols,aromatic heterocyclic alcohol respectively,increased steric hindrance and stability to look for substances with stronger activity,the study has ten AZ derivant included methanol ester,ethyl ester,n-butanol ester,isobutyl alcohol ester,phenol ester,p-chlorophenol ester of hydroquinone ester,methyl phenol ester,ethyl phenol esters,benzyl alcohol esters.By elemental analysis,HNMR(1HNMR),infrared spectroscopy(IR)and other equipment related data structures are confirmed.3.This experiment screened five AZ derivatives,study they pharmacodynamic,laid the foundation of clinical research for the AZderivatives.Establishing experimental rat hyperlipidemia model,measured and comparative analysised the related parameters by using ig administration,we found that AZ,AZ methanol ester,AZ ethanol ester,AZ phenol esters,AZ chlorophenol ester,AZ methylphenol ester can significantly reduce the levels of TC and LDL-C in hypercholesterolemic rats serum,therefore AZ derivatives can effectively regulate blood lipids,has a significant treatment effect on combined hyperlipidemia induced by high fat diet in rats. |
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