A New Thoyrid Hormone Receptor-β Agonist CS26087 Improves Non-Alcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease(NAFLD)is one of the most common liver diseases.The incidence rate of NAFLD has increased over the past 20 years,showing a tendency to become younger.NAFLD may further deteriorate into nonalcoholic steatohepatitis(NASH),liver cirrhosis,and even liver cancer.Among them,20% of NAFLD patients may develop into NASH,but there is no drug for NASH on the market,so it is urgent to develop drugs for NASH.At present,there are many drugs for NASH disease in research,and act on different targets.In this paper,the pharmacodynamics of a new thyroid receptor agonist(THR β)CS26087 in NASH animal model was studied.The drug was independently developed by Shenzhen micro core Biotechnology Co.,Ltd(1)Firstly,the synthesis steps and molecular structure of CS26087 were introduced.Because THRβ agonists may have an agonistic effect on THRα at the same time,which may lead to potential cardiac and skeletal toxicity.Therefore,the in vitro cell transfection assay was used to determine the activation of THRα and THRβ.CV-1 cells were transfected with THRα or THRβ vector and luciferase vector at the same time.The excitatory activity of CS26087 was determined by luciferase.The results showed that the EC50 of CS26087 for THRβ was 3.989 μM,and the selectivity of CS26087 for THRα / THRβ was 1.638 times.The EC50 of MGL-3196 was 9.566 μM,and the selectivity of MGL-3196 to THR α / THRβ was 71338 times.These results indicate that CS26087 has a certain selectivity for THRβ,while MGL-3196 has a good selectivity for THRβ.(2)The results showed that CS26087 was mainly targeted to the liver.The metabolism of CS26087 in vivo was determined by pharmacokinetic experiments.The results showed that CS26087 had a higher average retention time in SD rats than that of MGL-3196,and the effect of CS26087 was longer in vivo.Cmax of CS26087 was higher than that of positive drug in SD rats,AUC was slightly lower than that of positive drug.(3)In the mice model of methionine and choline deficiency diet(MCD),it was found that: CS26087 treated group mice could significantly improve liver steatosis(P < 0.01)and balloon like pathological score(P < 0.01).The results of these improvements were significantly better than that of the positive drug MGL-3196.(4)In the high fat diet(HFD)model of SD rats,it was found that after administration of CS26087 for four weeks,TC and LDL-C in serum decreased significantly(P < 0.01),and HDL-C decreased significantly(P < 0.05).However,the accumulation of TG and TC in the liver of CS26087 group was not significantly relieved.The results showed that the liver fat drop ratio,hepatitis score(P < 0.05)and fatty degeneration(P < 0.01)in CS26087 treatment group were significantly improved,but the score of hepatic gas globular change was improved but not significant.MGL-3196 treatment group also significantly improved serum TG,TC,HDL-C and LDL-C,and significantly improved the accumulation of TG and TC in liver,and also significantly improved the score of liver steatosis in rats.It is suggested that both CS26087 and MGL-3196 have potential for NASH disease treatment.