ABSTRACT
In an effort to develop safe and efficacious compounds for the treatment of metabolic disorders, novel thiophene substituted oxazole containing α-alkoxy-phenylpropanoic acid derivatives are designed as highly potent PPARα/γ dual agonists. These compounds were found to be efficacious at picomolar concentrations. Lead compound 18d has emerged as very potent PPARα/γ dual agonist demonstrating potent antidiabetic and lipid lowering activity at a very low dose and did not exhibit any significant signs of toxicity in rodents.
Subject(s)
PPAR alpha/agonists , PPAR gamma/agonists , Phenylpropionates/chemical synthesis , Phenylpropionates/pharmacology , Administration, Oral , Animals , Cell Line , Dose-Response Relationship, Drug , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Inhibitory Concentration 50 , Mice , Molecular Structure , Oxazoles/chemistry , Phenylpropionates/chemistry , Protein Binding/drug effects , Rats , Rats, Wistar , Rosiglitazone , Thiazolidinediones/chemical synthesis , Thiazolidinediones/chemistry , Thiazolidinediones/pharmacology , Thiophenes/chemistryABSTRACT
A series of novel 1,3-dioxane-2-carboxylic acid derivatives containing alkyl chain tether and substituted phenyl group as a lipophilic tail have been prepared as agonists of PPARalpha and gamma. c-5-[6-(4-Methanesulfonyloxyphenyl)hexyl]-2-methyl-1,3-dioxane-r-2-carboxylic acid 13c exhibited potent hypoglycemic and lipid lowering activity with high oral bioavailability in animal models.
