Thyroid hormone receptors (TRs) are a long-recognized target for hyperlipidemia, yet the therapeutic potential of selective TRß1 agonists remains unrealized in humans due to their concomitant undesired cardiovascular side effects. To increase the therapeutic index, phosphonic acid (PA) TR agonists were synthesized that were able to exploit the poor distribution of PA-based drugs to extra-hepatic tissues. Several PA TR agonists demonstrated excellent binding affinities (TRß1, Ki < 10 nM) and significant cholesterol lowering effects (cholesterol-fed rat, 0.2 mg/kg i.p.). Poor oral bioavailability of the lead PA MB07344 prompted synthesis of prodrugs, leading to identification of HepDirect prodrug MB07811 (rat ED50 = 0.5 mg/kg p.o.; F = 39%). Unlike T3 and the non-liver-selective TR agonist KB-141, MB07811 significantly reduced cholesterol and triglycerides (both serum and hepatic) in normal rats and diet-induced obese mice at doses devoid of effects on the heart, thyroid hormone axis, body weight, and glycemia.