Challenges in drug discovery for thiazolidinedione substitute  

作　　者：Jian-ping Ye 

机构地区：[1]Antioxidant and Gene Regulation Lab,Pennington Biomedical Research Center,Louisiana State University System,Baton Rouge,LA 70808,USA

出　　处：《Acta Pharmaceutica Sinica B》2011年第3期137-142,共6页药学学报（英文版）

基　　金：supported by NIH Grant DK068036 and DK085495 to J Ye.

摘　　要：Thiazolidinedione(TZD)is a powerful insulin sensitizer in the treatment of type 2 diabetes.It acts as a ligand to the nuclear receptor PPARγ(peroxisome proliferator-activated receptor-gamma)and induces transcription of PPARγ-responsive genes.TZD controls lipid synthesis and storage in adipose tissue,liver and many other tissues through PPARg.Derivatives of TZD,such as rosiglitazone(Avandia)and pioglitazone(Actos),are more powerful than metformin or berberine in insulin sensitization.Although they have common side effects such as weight gain and edema,these did not influence their clinical application in general.However,recent findings of risk for congestive heart failure and bladder cancer have significantly impaired their future in many countries.European countries have prohibited those drugs,and US will terminate application of rosiglitazone in clinics and hospitals.The multiple country actions may mark the end of TZD era.As a result,there is a strong demand for identification of TZD substitute in the treatment of type 2 diabetes.In this regard,literature about PPARγ ligands and potential TZD substitute are reviewed in this article.Histone deacetylase(HDAC)inhibitor is emphasized as a new class of insulin sensitizer here.Regulators of SIRT1,CREB,NO,p38,ERK and Cdk5 are discussed in the activation of PPARγ.

关 键 词：PPARγligands THIAZOLIDINEDIONE Type 2 diabetes Insulin sensitizer Side effect Histone deacetylase inhibitor 

分 类 号：R73[医药卫生—肿瘤]