ABSTRACT
Specific retinoid X receptor (RXR) agonists, such as LG100268 (LG268), and the thiazolidinedione (TZD) PPARgamma agonists, such as rosiglitazone, produce insulin sensitization in rodent models of insulin resistance and type 2 diabetes. In sharp contrast to the TZDs that produce significant increases in body weight gain, RXR agonists reduce body weight gain and food consumption. Unfortunately, RXR agonists also suppress the thyroid hormone axis and generally produce hypertriglyceridemia. Heterodimer-selective RXR modulators have been identified that, in rodents, retain the metabolic benefits of RXR agonists with reduced side effects. These modulators bind specifically to RXR with high affinity and are RXR homodimer partial agonists. Although RXR agonists activate many heterodimer partners, these modulators selectively activate RXR:PPARalpha and RXR:PPARgamma, but not RXR:RARalpha, RXR:LXRalpha, RXR:LXRbeta, or RXR:FXRalpha. We report the in vivo characterization of one RXR modulator, LG101506 (LG1506). In Zucker fatty (fa/fa) rats, LG1506 is a potent insulin sensitizer that also enhances the insulin-sensitizing activities of rosiglitazone. Administration of LG1506 reduces both body weight gain and food consumption and blocks the TZD-induced weight gain when coadministered with rosiglitazone. LG1506 does not significantly suppress the thyroid hormone axis in rats, nor does it elevate triglycerides in Sprague Dawley rats. However, LG1506 produces a unique pattern of triglycerides elevation in Zucker rats. LG1506 elevates high-density lipoprotein cholesterol in humanized apolipoprotein A-1-transgenic mice. Therefore, selective RXR modulators are a promising approach for developing improved therapies for type 2 diabetes, although additional studies are needed to understand the strain-specific effects on triglycerides.
Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Fatty Acids, Unsaturated/administration & dosage , Hypoglycemic Agents/administration & dosage , Obesity/drug therapy , Phenyl Ethers/administration & dosage , Retinoid X Receptors/agonists , Thiazolidinediones/administration & dosage , Analysis of Variance , Animals , Apolipoprotein A-I/genetics , Apolipoprotein A-I/physiology , Area Under Curve , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/complications , Dose-Response Relationship, Drug , Drug Interactions , Female , Hypoglycemic Agents/therapeutic use , Mice , Mice, Transgenic , Obesity/blood , Obesity/complications , PPAR gamma/agonists , PPAR gamma/metabolism , Rats , Rats, Sprague-Dawley , Rats, Zucker , Retinoid X Receptors/metabolism , Rosiglitazone , Statistics, Nonparametric , Thiazolidinediones/pharmacology , Thiazolidinediones/therapeutic use , Thyroid Gland/drug effects , Triglycerides/bloodABSTRACT
The synthesis and in vitro characterization of novel RXR-selective ligands possessing various substituted 1-benzofuran or 1-benzothiophene moieties are described.
Subject(s)
Drug Design , Receptors, Retinoic Acid/metabolism , Transcription Factors/metabolism , Tretinoin/analogs & derivatives , Tretinoin/metabolism , Protein Binding/physiology , Retinoid X Receptors , Structure-Activity RelationshipABSTRACT
Retinoid X receptor:peroxisome proliferative-activated receptor (RXR:PPAR) heterodimers play a critical role in the regulation of glucose (RXR/PPARgamma) and lipid metabolism (RXR/PPARalpha). Previously, we described a concise structure-activity relationship study of selective RXR modulators possessing a (2E,4E,6Z)-3-methyl-7-(3,5-dialkyl-6-alkoxyphenyl)-octa-2,4,6-trienoic acid scaffold. These studies were focused on the 2-position alkoxy side chain. We describe here the design and synthesis of a novel series of RXR selective modulators possessing the same aromatic core structure with the addition of a ring locked 6-7-Z-olefin on the trienoic acid moiety. The synthesis and structure-activity relationship studies of these 6,7-locked cyclopentenyl, phenyl, thienyl, furan, and pyridine-trienoic acid derivatives is presented herein.
