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Submitted on July 30, 2003
Accepted on December 19, 2003
1 Metabolic and Cardiovascular Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Pennington, N.J. USA; Departments of Pharmaceutical Chemistry and Cellular & Molecular Pharmacology, University of California-San Francisco, San Francisco, CA; Metabolic Research Unit, University of California San Francisco, San Francisco, CA.
* To whom correspondence should be addressed. 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 non-selective thyromimetics are not clinically useful for such treatment due to cardiac side-effects. Recent studies suggest that thyroid hormone receptor subtype 
(TR) 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 following TR stimulation. For these studies, the TR 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 day treatment) showed that GC-1 reduced cholesterol (ED50 = 190 nmol/kg/day) approximately 30-times more potently than it induced tachycardia (ED15 = 5451 nmol/kg/day). Triiodothyronine (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/day) relative to tachycardia compared with T3 which showed no selectivity. In cynomolgus monkeys treated for 7 days, significant cholesterol-lowering and Lp(a) reduction was noted for both T3 and GC-1, while no tachycardia was observed for GC-1, unlike T3. T3 and GC-1 caused a significant (approximately 4%) reduction in body weight in these animals. Therefore selective TR activation may be a potentially usefully treatment for obesity and reduction of LDL-cholesterol and reduction of the atherogenic risk factor Lp(a).
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