5-Aryl thiazolidine-2,4-diones: discovery of PPAR dual α/γ agonists as antidiabetic agents

• Published in: Bioorganic & medicinal chemistry letters Vol. 13; no. 16; pp. 2795 - 2798
• Main Authors: Desai, Ranjit C., Han, Wei, Metzger, Edward J., Bergman, Jeffrey P., Gratale, Dominick F., MacNaul, Karen L., Berger, Joel P., Doebber, Thomas W., Leung, Kwan, Moller, David E., Heck, James V., Sahoo, Soumya P.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 18.08.2003; Elsevier
• Subjects: Administration, Oral; Animals; Biological and medical sciences; Diabetes Mellitus, Type 2 - drug therapy; Disease Models, Animal; General and cellular metabolism. Vitamins; Hyperglycemia - drug therapy; Hypertriglyceridemia - drug therapy; Hypoglycemic Agents - chemical synthesis; Hypoglycemic Agents - pharmacology; Medical sciences; Mice; Pharmacology. Drug treatments; Receptors, Cytoplasmic and Nuclear - agonists; Receptors, Cytoplasmic and Nuclear - metabolism; Rosiglitazone; Structure-Activity Relationship; Thiazolidinediones - chemical synthesis; Thiazolidinediones - pharmacology; Transcription Factors - agonists; Transcription Factors - metabolism; Endocrinopathy; Agonist; Intravenous administration; Rat; Clearance; Non insulin dependent diabetes; PPAR-α receptor; Hypoglycemic agent; Structure activity relation; Chlorine Organic compounds; Area under the curve; Diether; Chemical synthesis; Sulfur nitrogen heterocycle; Rodentia; Oral administration; Thiazolidinedione derivatives; Bioavailability; PPAR-γ receptor; Triglyceride; In vitro; In vivo; Vertebrata; Mammalia; Mouse; Animal; Rosiglitazone; Benzenic compound; Fluorine Organic compounds; Pharmacokinetics; Antilipemic agent
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(03)00505-5

A novel series of 5-aryl thiazolidine-2,4-diones based dual PPARα/γ agonists was identified. A number of highly potent and orally bioavailable analogues were synthesized. Efficacy study results of some of these analogues in the db/db mice model of type 2 diabetes showed them superior to rosiglitazone in correcting hyperglycemia and hypertriglyceridemia. A novel series of potent, orally efficacious dual PPAR α/γ agonists was identified.