Novel thiazolidinedione derivatives with anti-obesity effects: Dual action as PTP1B inhibitors and PPAR-gamma activators

作者：Bhattarai Bharat Raj; Kafle Bhooshan; Hwang Ji Sun; Ham Seung Wook; Lee Keun Hyeung; Park Hwangseo; Han Inn Oc^*; Cho Hyeongjin

来源：Bioorganic & Medicinal Chemistry Letters, 2010, 20(22): 6758-6763.

DOI：10.1016/j.bmcl.2010.08.130

• Protein tyrosine phosphatase
• Thiazolidinedione
• PTP1B inhibitor
• PPAR-gamma activator
• Anti-obesity

Benzylidene-2,4-thiazolidinedione derivatives with substitutions at both the ortho and para-positions of the phenyl group were synthesized as PTP1B inhibitors with IC(50) values in a low micromolar range. Compound 18l, the lowest, bore an IC(50) of 1.3 mu M. In a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) promoter reporter gene assay, 18l was found to activate the transcription of the reporter gene with potencies comparable to those of troglitazone, rosiglitazone, and pioglitazone. In vivo efficacy of 18l as an anti-obesity and hypoglycemic agent was evaluated in a mouse model system. Compound 18l significantly suppressed weight gain and significantly improved blood parameters such as TG, total cholesterol and NEFA without overt toxic effects.

• 出版日期2010-11-15