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Effects of the Thyroid Hormone Receptor Agonist GC-1 on Metabolic Rate and Cholesterol in Rats and Primates: Selective Actions Relative to 3,5,3'-Triiodo-L-Thyronine

Metabolic and Cardiovascular Drug Discovery (G.J.G., D.M.E., P.G.S., B.C.B.), Bristol-Myers Squibb Pharmaceutical Research Institute, Pennington, New Jersey 08534; and Departments of Pharmaceutical Chemistry and Cellular and Molecular Pharmacology (N.-H.N., T.S.S.) and the Metabolic Research Unit (J.D.B.), University of California, San Francisco, San Francisco, California 94143

Address all correspondence and requests for reprints to: Gary J. Grover, Ph.D., Metabolic and Cardiovascular Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Pennington, New Jersey 08534. E-mail: groverg{at}bms.com.

Current drug therapies for obesity are ineffective, and existing treatments for lipid disorders can be further improved. Thyroid hormones affect both conditions, although currently available nonselective thyromimetics are not clinically useful for such treatment due to cardiac side effects. Recent studies suggest that thyroid hormone receptor subtype ß (TRß) selective agonists have a profile in which cholesterol can be reduced with minimal tachycardia. The purpose of this study was to determine whether modest (5–10%) increases in metabolic rate could also be observed with minimal tachycardia after TRß stimulation. For these studies, the TRß selective agonist, GC-1, was used to assess selectivity for lipid-lowering and metabolic rate changes relative to tachycardia. Studies in cholesterol-fed rats (7 d treatment) showed that GC-1 reduced cholesterol (ED₅₀ = 190 nmol/kg·d) approximately 30 times more potently than it induced tachycardia (ED₁₅ = 5451 nmol/kg·d). T₃ showed no potency difference between cholesterol lowering and tachycardia. GC-1 showed approximately 10-fold selectivity for increasing metabolic rate (ED₅ = 477 nmol/kg·d) relative to tachycardia compared with T₃, which showed no selectivity. In cynomolgus monkeys treated for 7 d, significant cholesterol-lowering and lipoprotein (a) reduction was noted for both T₃ and GC-1, whereas no tachycardia was observed for GC-1, unlike T₃. T₃ and GC-1 caused a significant (4%) reduction in body weight in these animals. Therefore, selective TRß activation may be a potentially usefully treatment for obesity and reduction of low density lipoprotein cholesterol and reduction of the atherogenic risk factor lipoprotein (a).

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