Novel thiazolidinedione derivatives with anti-obesity effects: dual action as PTP1B inhibitors and PPAR-γ activators.
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 μM. In a peroxisome proliferator-activated receptor-γ (PPAR-γ) 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.
Bhattarai
Bharat Raj
BR
Department of Chemistry, Inha University, Incheon 402-751, Republic of Korea.
Kafle
Bhooshan
B
Hwang
Ji-Sun
JS
Ham
Seung Wook
SW
Lee
Keun-Hyeung
KH
Park
Hwangseo
H
Han
Inn-Oc
IO
Cho
Hyeongjin
H
D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology*; D001786:Blood Glucose / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D005230:Fatty Acids, Nonesterified / Q000097:blood; D007004:Hypoglycemic Agents / Q000494:pharmacology; D051379:Mice; D047495:PPAR gamma / Q000819:agonists*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors*; D045162:Thiazolidinediones / Q000494:pharmacology*; D014280:Triglycerides / Q000097:blood
D019440:Anti-Obesity Agents; D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D014280:Triglycerides; D002784:Cholesterol; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1