SYNTHESIS AND BIOLOGICAL-ACTIVITY OF METABOLITES OF THE ANTIDIABETIC,ANTIHYPERGLYCEMIC AGENT PIOGLITAZONE

Pioglitazone yl-2-pyridyl)ethoxy)benzyl)-2,4-thiazolidinedione, 2) is a prototypical antidiabetic thiazolidinedione that had been evaluated for possible; clinical development. Metabolites 6-9 have been identifi ed after dosing of rats and dogs. Ketone 10 has not yet been identifie d as a metabolite but has been added to the list as a putative metabol ite by analogy to alcohol 6 and ketone 7. We have developed improved s yntheses of pioglitazone (2) metabolites 6-9 and the putative metaboli te ketone 10. These entities have been compared in the KKA(y) mouse mo del of human type-II diabetes to pioglitazone (2). Ketone 10 has prove n to be the most potent of these thiazolidinediones in this in, vivo a ssay. When 6-10 were compared in vitro in the 3T3-L1 cell line to 2, f or their ability to augment insulin-stimulated lipogenesis, 10 was aga in the most potent compound with 6, 7, and 9 roughly equivalent to 2. These data suggest that metabolites 6, 7, and 9 are likely to contribu te to the pharmacological activity of pioglitazone (2), as had been pr eviously reported for ciglitazone (1).