Evaluation Of The Biological Activity Of A New Lipid-lowering Drug XH-1273

Background:Natural isoflavone has been reported for the blood lipid lowering activity.But natural isoflavone has limited resource,and it is not easy to extract and separate.Our group synthesized series new compounds based on isoflavone,XH-1273 showed good lipid lowering activity during preliminary screening.This study was designed for further investigation of XH-1273 on obesity and hyperlipidemia in vivo and in vitro.Methods:（1）Effect of XH-1273 on 3T3-L1 cells viability and differentiation were detected by MTT method and Oil-Red-staining respectively.（2）SD rats were divided into seven group（n=10）,the normal group,the model grop,the XH-1273 10,20,25 mg/kg group,the Simvastatin group,the Hepoxal group.One intrapertioneal injection of poloxamer 407（300mg/kg）induced a short-term hyperlipidemia of SD rats.Blood samples were collected prior topoloxamer 407injection,3h,24h after the injection.Serum TC,TG and LDLC concentration were determined by a microplate reader.（3）10 weeks high fat diet induced rabbits obesity and hyperlipidemia.And then the rabbits were given 9 weeks treatment with 20 mg/kg XH-1273.Fasted blood samples were collected every Tuesday morning,serum TC,TG and LDLC concentration of rabbits were determined by a microplate reader.Results:（1）XH-1273 concentration-dependent inhibited the viability of 3T3-L1 cell,when the drug concentration arrived 1×10^-4mol/L,the inhibiton ratio were 73.1%.（2）XH-1273 reduced the lipid accumulation in the differentiation of 3T3-L1preadipocyte,the lipid concentration in cells droped 36.4%.（3）One intrapertioneal injection of poloxamer 407（300mg/kg）induced a short-term hyperlipidemia of SD rats successfully.Serum TC,TG and LDLC of the model group at 24h after injection were 5.7,25.0 and 3.62fold of the normal group.（4）XH-1273 reversed the effect of poloxamer 407 on serm lipid of SD Rats.Different dosage of XH-1273 showed different levels reduction of rats serum lipid profile.The group given XH-1273 10mg/kg,serum TC and TG decreased 24.1%and56.3%respectively.The group given XH-1273 20mg/kg,serum TC and LDLC decreased 32.9%and 65.6%respectively.The group given XH-1273 25mg/kg,serum TC and TG decreased 48.2%and 54.9%respectively.（5）10 weeks high fat diet induced rabbits obesity and hyperlipidemia successfully.Serum TC,TG and LDLC of rabbits at 10 weeks were 63.8,2.0 and 40.1 fold of the first week,and rabbits weight increased 79.5%.（6）Serum TC,TG and LDLC and weight of the rabbits decreased significantly after 9 weeks treatment of XH-1273.When compared with the 10 week,Serum TC,TG and LDLC decreased 45.3%,43.7%and 36.0%respectively,and the weight droped 10.1%Conclusion:XH-1273 inhibit the viability and diffentiation of 3T3-L1,reduce the quantity and quality of adipocyte,and then decrease adipocyte tissue volume.XH-1273 reduce lipid profile of rats and rabbits hyperlipidemia significantly,it also help obesity rabbits lose weight.XH-1273 is a candidate drug for obesity and hyperlipidemia,and it beneficial to atherosclerosis.