Novel 5-Substituted-1H-tetrazole Derivatives as Potent Glucose and Lipid Lowering Agents

抄録

A series of 5-(4-alkoxyphenylalkyl)-1H-tetrazole derivatives, containing an oxazole-based group at the alkoxy moiety, was prepared and their antidiabetic effects were evaluated in two genetically obese and diabetic animal models, KKA^y mice and Wistar fatty rats. Syntheses were performed by cyclization of the corresponding nitriles reacting with azide compounds. A large number of the 5-(4-alkoxyphenylalkyl)-1H-tetrazoles showed potent glucose and lipid lowering activities in KKA^y mice. In particular, 5-[3-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridyl]propyl]-1H-tetrazole had potent glucose lowering activity (ED₂₅=0.0839 mg⋅kg⁻¹⋅d⁻¹), being 72 times more active than pioglitazone hydrochloride (ED₂₅=6.0 mg⋅kg⁻¹⋅d⁻¹). This compound also showed strong glucose lowering (ED₂₅=0.0873 mg⋅kg⁻¹⋅d⁻¹) and lipid lowering effects (ED₂₅=0.0277 mg⋅kg⁻¹⋅d⁻¹) in Wistar fatty rats. The antidiabetic effects of this compound are considered to be due to its potent agonistic activity for peroxisome proliferator-activated receptor γ (PPARγ) (EC₅₀=6.75 nM).