Abstract
Benzylidene-2,4-thiazolidinedione derivatives with substitutions on the phenyl ring at the ortho or para positions of the thiazolidinedione (TZD) group were synthesized as PTP1B inhibitors with IC50 values in a low micromolar range. Compound 3e, the lowest, bore an IC50 of 5.0 microM. In vivo efficacy of 3e as an antiobesity and hypoglycemic agent was evaluated in a mouse model system. Significant improvement of glucose tolerance was observed. This compound also significantly suppressed weight gain and significantly improved blood parameters such as TG, total cholesterol and NEFA. Compound 3e was also found to activate peroxisome proliferator-activated receptors (PPARs) indicating multiple mechanisms of action.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Anti-Obesity Agents / chemical synthesis
-
Anti-Obesity Agents / chemistry*
-
Anti-Obesity Agents / pharmacology
-
Binding Sites
-
Blood Glucose / metabolism
-
Catalytic Domain
-
Computer Simulation
-
Enzyme Inhibitors / chemical synthesis
-
Enzyme Inhibitors / chemistry*
-
Enzyme Inhibitors / pharmacology
-
Hypoglycemic Agents / chemical synthesis
-
Hypoglycemic Agents / chemistry*
-
Hypoglycemic Agents / pharmacology
-
Mice
-
PPAR gamma / antagonists & inhibitors
-
PPAR gamma / metabolism
-
Phenyl Ethers / chemical synthesis
-
Phenyl Ethers / chemistry*
-
Phenyl Ethers / pharmacology
-
Protein Tyrosine Phosphatase, Non-Receptor Type 1 / antagonists & inhibitors*
-
Protein Tyrosine Phosphatase, Non-Receptor Type 1 / metabolism
-
Thiazolidinediones / chemical synthesis
-
Thiazolidinediones / chemistry*
-
Thiazolidinediones / pharmacology
Substances
-
Anti-Obesity Agents
-
Blood Glucose
-
Enzyme Inhibitors
-
Hypoglycemic Agents
-
PPAR gamma
-
Phenyl Ethers
-
Thiazolidinediones
-
Protein Tyrosine Phosphatase, Non-Receptor Type 1
-
Ptpn1 protein, mouse