Docking, Synthesis and Anti-Diabetic Activity of Novel Sulfonylhydrazone Derivatives Designed as PPAR-Gamma Agonists
| Autor: | Eliezer J. Barreiro, Nelilma C. Romeiro, Lídia Moreira Lima, Roberto T. Sudo, Margarete M. Trachez, Everton D. D’Andrea, Filipe P. da Costa, Gisele Zapata-Sudo, Beatriz J. Souza, Carlos Eduardo da Silva Monteiro, Sharlene L Pereira |
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| Rok vydání: | 2012 |
| Předmět: |
Models
Molecular medicine.medical_specialty Diabetic neuropathy Peroxisome proliferator-activated receptor Streptozocin Diabetes Mellitus Experimental Mice Internal medicine Diabetes mellitus Drug Discovery medicine Animals Hypoglycemic Agents Receptor chemistry.chemical_classification Glucose tolerance test medicine.diagnostic_test business.industry Metabolic disorder Hydrazones General Medicine Glucose Tolerance Test medicine.disease Molecular Docking Simulation PPAR gamma Endocrinology chemistry Docking (molecular) Thermodynamics business |
| Zdroj: | Current Topics in Medicinal Chemistry. 12:2037-2048 |
| ISSN: | 1568-0266 |
| DOI: | 10.2174/156802612804910205 |
| Popis: | Diabetes is a metabolic disorder characterized by hyperglycemia. When not properly controlled, complications include neuropathy, coronary artery disease, and renal failure. Several drugs are approved for diabetes treatment; however their use is associated with side effects and lack of efficacy in attenuating the development of long-term complications. This work describes the virtual screening and synthesis of a novel series of sulfonylhydrazone derivatives designed as peroxisome proliferator-activated receptor gamma (PPARγ) agonists and investigation of the analogs for hypoglycemic activity in a murine model of diabetes. Docking studies identified LASSBio-331 (5) as having theoretical affinity for PPARγ similar to the prototype (S)-rosiglitazone. Several structural modifications were proposed for the structure of LASSBio-331, resulting in the synthesis of five novel compounds, which showed experimental affinity for PPARγ. Among these new compounds, LASSBio-1471 (15) had the best theoretical binding energy for PPARγ and was selected for testing in STZ-induced diabetes. Four weeks after single intravenous injection of STZ (60 mg/kg), Wistar rats were treated with vehicle (DMSO) or LASSBio-1471 (20 mg/kg, i.p.) for 7 days. The blood glucose levels of rats treated with LASSBio-1471 were reduced from 548.4 ± 26.0 mg/dL before treatment to 259.6 ± 73.1 mg/dL (P < 0.05). Paw withdrawal threshold was significantly reduced in diabetic rats and was restored from 21.9 ± 1.7 g to 36.7 ± 1.2 g after 7 days of treatment with LASSBio-1471 (P < 0.05). Thus, the novel sulfonylhydrazone derivative is a PPARγ ligand that is effective for treatment of diabetic neuropathy in STZ-injected rats. |
| Databáze: | OpenAIRE |
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