Biol. Pharm. Bull. 28(7) 1192—1196 (2005)

receptors called peroxisome proliferator-activated receptors (PPARs) have opened up the possibilities for treatment of many metabolic diseases including type 2 diabetes. PPARs have three subtypes, i.e. PPARa , PPARd , and PPARg . PPARs modulate expression of genes involved in the transport and metabolism of glucose and lipids. PPARa is mainly expressed in tissues such as liver, which is activated by a class of ligands named fibrates that are known to have triglycerideand cholesterol-lowering activity. PPARd regulates fat metabolism and may serve as a potential target in treatment of obesity and its associated disorders. Activation of PPARg mediates adipocyte differentiation and storage of free fatty acids primarily into adipose tissue, and the PPARg agonists have been widely used in treatment of type 2 diabetes. All three PPARs form heterodimers with another nuclear receptor, retinoid X receptor (RXR). RXR/PPARs belong to permissive RXR heterodimers which can be activated by either an RXR or a PPAR subtype-specific ligand. Synthetic compounds binding to either RXR/RXR homodimers or RXR/PPARg heterodimers have been shown to relieve insulin resistance in various animal models of type 2 diabetes. Those compounds include the RXR/RXR antagonist LG100754, and the well known RXR/PPARg agonists thiazolidinediones (TZDs, for example, rosiglitazone). Thus, synthesis and characterization of novel compounds acting on either RXR/RXR and/or RXR/PPARs will be a reasonable strategy to discover the potential drug leads for the treatment of metabolic diseases. Based on the chemical structure of the RXR natural ligand, 9-cis-retinoic acid (9-cis-RA), we designed and synthesized a retinoid-like compound, CS018. To evaluate whether CS018 could be further developed as a drug lead for the treatment of type 2 diabetes, we have characterized the properties of CS018 in activation of RXR-related receptors in vitro, and observed its blood glucose-lowering effect in vivo, as reported in the present study. MATERIALS AND METHODS