Design, synthesis and biological evaluation of thiazole- and indole-based derivatives for the treatment of type II diabetes

Qinyuan Xu; Li Huang; Juan Liu; Liang Ma; Tao Chen; Jinying Chen; Fei Peng; Dong Cao; Zhuang Yang; Neng Qiu; Jingxiang Qiu; Guangcheng Wang; Xiaolin Liang; Aihua Peng; Mingli Xiang; Yuquan Wei; Lijuan Chen

doi:10.1016/j.ejmech.2012.03.006

Design, synthesis and biological evaluation of thiazole- and indole-based derivatives for the treatment of type II diabetes

Eur J Med Chem. 2012 Jun:52:70-81. doi: 10.1016/j.ejmech.2012.03.006. Epub 2012 Mar 13.

Authors

Qinyuan Xu¹, Li Huang, Juan Liu, Liang Ma, Tao Chen, Jinying Chen, Fei Peng, Dong Cao, Zhuang Yang, Neng Qiu, Jingxiang Qiu, Guangcheng Wang, Xiaolin Liang, Aihua Peng, Mingli Xiang, Yuquan Wei, Lijuan Chen

Affiliation

¹ State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Keyuan Road 4, Gaopeng Street, Chengdu 610041, China.

PMID: 22483089
DOI: 10.1016/j.ejmech.2012.03.006

Abstract

Present studies have shown that the lipid carrier has a significant role in several aspects of metabolic syndrome in A-FABP/ap2-deficient mice, including type 2 diabetes and atherosclerosis. 38 Thiazole- and indole-based derivatives were synthesized and investigated for their inhibitory effects on the production of LPS-stimulated TNF-α. Among them, 12b exhibited an excellent inhibitory efficiency compared to BMS309403 (95% vs. 85%) at the concentration of 10 μM and a binding affinity for ap2 with the apparent K(i) values 33 nM. Oral administration of 12b at a dosage of 50 mg/kg effectively reduced the levels of plasma blood glucose, triglycerides, insulin, total cholesterol and alanine aminotransferase in high-fat/diet-induced obesity model. The results highlighted that 12b was a potent anti-diabetic agent.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Administration, Oral
Alanine Transaminase / metabolism
Animals
Blood Glucose / metabolism
Body Weight / drug effects
Cell Line
Cholesterol / blood
Diabetes Mellitus, Type 2 / blood
Diabetes Mellitus, Type 2 / drug therapy*
Diabetes Mellitus, Type 2 / metabolism
Diabetes Mellitus, Type 2 / physiopathology
Drug Design*
Fatty Acid-Binding Proteins / chemistry
Fatty Acid-Binding Proteins / metabolism
Hypoglycemic Agents / chemical synthesis
Hypoglycemic Agents / chemistry
Hypoglycemic Agents / pharmacology
Hypoglycemic Agents / therapeutic use
Indoles / chemical synthesis
Indoles / chemistry*
Indoles / pharmacology*
Indoles / therapeutic use
Insulin / blood
Lipopolysaccharides / pharmacology
Male
Mice
Models, Molecular
Protein Conformation
Rats
Structure-Activity Relationship
Thiazoles / chemical synthesis
Thiazoles / chemistry*
Thiazoles / pharmacology*
Thiazoles / therapeutic use
Triglycerides / blood
Tumor Necrosis Factor-alpha / biosynthesis

Substances

Blood Glucose
FABP4 protein, rat
Fatty Acid-Binding Proteins
Hypoglycemic Agents
Indoles
Insulin
Lipopolysaccharides
Thiazoles
Triglycerides
Tumor Necrosis Factor-alpha
Cholesterol
Alanine Transaminase