title: Synthesis and biological activity of metabolites of the antidiabetic, antihyperglycemic agent pioglitazone.
abstract: Pioglitazone (5-(4-(2-(5-ethyl-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 identified after dosing of rats and dogs. Ketone 10 has not yet been identified as a metabolite but has been added to the list as a putative metabolite by analogy to alcohol 6 and ketone 7. We have developed improved syntheses of pioglitazone (2) metabolites 6-9 and the putative metabolite ketone 10. These entities have been compared in the KKAy mouse model of human type-II diabetes to pioglitazone (2). Ketone 10 has proven to be the most potent of these thiazolidinedinediones in this in vivo assay. When 6-10 were compared in vitro in the 3T3-L1 cell line to 2, for their ability to augment insulin-stimulated lipogenesis, 10 was again 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 contribute to the pharmacological activity of pioglitazone (2), as had been previously reported for ciglitazone (1).
authors.affiliation: Department of Discovery Chemistry, Upjohn Laboratories, Pharmacia and Upjohn, Inc., Kalamazoo, Michigan 49001, USA.
authors.forename: S P
authors.initials: SP
authors.lastname: Tanis
authors.forename: T T
authors.initials: TT
authors.lastname: Parker
authors.forename: J R
authors.initials: JR
authors.lastname: Colca
authors.forename: R M
authors.initials: RM
authors.lastname: Fisher
authors.forename: R F
authors.initials: RF
authors.lastname: Kletzein
mesh_terms: D000818:Animals; D004285:Dogs; D006207:Half-Life; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D007333:Insulin Resistance; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D000077205:Pioglitazone; D051381:Rats; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D045162:Thiazolidinediones
chemical_list: D007004:Hypoglycemic Agents; D013844:Thiazoles; D045162:Thiazolidinediones; D000077205:Pioglitazone