Various analogues of a new antidiabetic agent, pioglitazone (AD-4833, U-72107), were synthesized in order to study in more detail the structure-activity relationships of this class of drug. 5-(4-Pyridylalkylthiobenzyl)-2, 4-thiazolidinediones (I), thia-analogues of pioglitazone, were prepared via Meerwein arylation of teh alkylthioanilines (IV). 5-(4-Pyridylalkoxybenzylidene)-2, 4-thiazolidinediones (IIa) and related heterocyclic analogues (IIb) were synthesized by Knoevenagel condensation of the aldehydes (VIII) with the corresponding azolidinones. Compounds I and II were evaluated for hypoglycemic and hypolipidemic activity in genetically obese and diabetic yellow KK (KKA^y) mice. Several 5-[4-[2-(2-pyridyl)ethoxy]-benzylidene]-2, 4-thiazolidinediones (IIa) were equipotent to pioglitazone. However, the thia-analogues (I) and teh benzylideneheterocycles (IIb) had decreased activity. Catalytic hydrogenation of the 5-benzylidene analogue (14) was found to be a convenient new synthetic method for pioglitazone. The configuration of 14 is also discussed.