For some time, researchers have been trying to develop therapeutic agents with the same kind of lipid-lowering activity that natural thyroid hormone has when it activates receptors in the liver. But the agents that have been identified so far cause serious side effects such as heart problems, muscle wasting, and bone loss because they activate thyroid hormone receptors not only in the liver but also in other organs. Mark D. Erion and coworkers at Metabasis Therapeutics, La Jolla, Calif., now have found the first compound that selectively targets thyroid hormone receptors in the liver (Proc. Natl. Acad. Sci. USA, DOI: 10.1073/pnas.0702759104). By screening a library of phosphonate-containing analogs, the researchers identified a lead compound and then modified it to enhance its oral availability and liver-targeting properties. The resulting prodrug (shown), which assumes an active form when the terminal rings to the right of the phosphonate are cleaved enzymatically in the liver, reduces cholesterol and triglyceride levels in mice without side effects. It's now in human clinical trials for reducing cholesterol.