Thiazolidinedione derivatives as PTP1B inhibitors with antihyperglycemic and antiobesity effects.
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.
Department of Chemistry, Inha University, Incheon 402-751, Republic of Korea.
Bharat Raj
BR
Bhattarai
Bhooshan
B
Kafle
Ji-Sun
JS
Hwang
Deegendra
D
Khadka
Sun-Myung
SM
Lee
Jae-Seung
JS
Kang
Seung Wook
SW
Ham
Inn-Oc
IO
Han
Hwangseo
H
Park
Hyeongjin
H
Cho
D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D001786:Blood Glucose / Q000378:metabolism; D020134:Catalytic Domain; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051379:Mice; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000378:metabolism; D010647:Phenyl Ethers / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045162:Thiazolidinediones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
D019440:Anti-Obesity Agents; D001786:Blood Glucose; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D010647:Phenyl Ethers; D045162:Thiazolidinediones; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C516609:Ptpn1 protein, mouse