Docking, Synthesis and Anti-Diabetic Activity of Novel Sulfonylhydrazone Derivatives Designed as PPAR-Gamma Agonists

作者：Zapata Sudo Gisele^*; Lima Lidia M; Pereira Sharlene L; Trachez Margarete M; da Costa Filipe P; Souza Beatriz J; Monteiro Carlos E S; Romeiro Nelilma C; D' Andrea Everton D; Sudo Roberto T; Barreiro Eliezer J

来源：Current Topics in Medicinal Chemistry, 2012, 12(19): 2037-2048.

DOI：10.2174/156802612804910205

• Diabetic neuropathy
• virtual screening
• sulfonylhydrazone
• hypoglycemic activity
• PPAR gamma

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 (PPAR gamma) 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 PPAR gamma 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 PPAR gamma. Among these new compounds, LASSBio-1471 (15) had the best theoretical binding energy for PPAR gamma 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 %26lt; 0.05). Paw with-drawal 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 %26lt; 0.05). Thus, the novel sulfonylhydrazone derivative is a PPAR ligand that is effective for treatment of diabetic neuropathy in STZ-injected rats.

• 出版日期2012-10