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Biological Characterization of a Heterodimer-Selective Retinoid X Receptor Modulator: Potential Benefits for the Treatment of Type 2 Diabetes

Ligand Pharmaceuticals (M.D.L., R.J.A., M.F.B., D.L.C., J.D., N.I.H., R.A.H., D.J., K.K., S.L., D.E.M., C.M.M., K.B.M., P.-Y.M., K.M.O., B.P., D.R., J.S.T., M.S.U., M.W.), San Diego, California 92121; and Lilly Research Laboratories (C.L.B., M.A.C., G.J.E., M.M.F., T.A.G., H.H., C.M.-R., N.Y., A.R.-M.), Indianapolis, Indiana 46285

Address all correspondence and requests for reprints to: Dr. Mark D. Leibowitz, Ligand Pharmaceuticals, Inc., 10275 Science Center Drive, San Diego, California 92121. E-mail: mleibowitz{at}ligand.com.

Specific retinoid X receptor (RXR) agonists, such as LG100268 (LG268), and the thiazolidinedione (TZD) PPAR 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:PPAR and RXR:PPAR, but not RXR:RAR, RXR:LXR, RXR:LXRß, or RXR:FXR. 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.

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