Abstract
A potent lipid-lowering thyromimetic (CGS 26214) devoid of cardiac and thermogenic activity was identified based on its ability to preferentially access and bind the nuclear fraction of hepatocytes over that of myocytes in culture. The difference in access achieved with CGS 26214 was at least 100-fold better for hepatocytes than for myocytes. This in vitro hepatoselectivity resulted in a compound with unprecedented in vivo lipid-lowering potency with a minimal effective dose of 1 microgram/kg in rats and dogs (approximately 25x that of L-T3). At the same time, CGS 26214 was free of any cardiovascular effects up to the highest dose tested of 25 mg/kg and 100 micrograms/kg in rats and dogs, respectively.
MeSH terms
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Animals
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Animals, Newborn
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Anticholesteremic Agents / metabolism
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Anticholesteremic Agents / pharmacology
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Binding, Competitive
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Body Temperature / drug effects*
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Carcinoma, Hepatocellular / pathology
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Cardiac Output / drug effects
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Cardiovascular System / drug effects*
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Cell Nucleus / drug effects
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Cell Nucleus / metabolism
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Cholesterol / blood
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Dogs
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Drug Evaluation, Preclinical
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Glyoxylates / metabolism
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Glyoxylates / pharmacology*
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Heart / drug effects
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Hypercholesterolemia / blood
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Hypolipidemic Agents / metabolism
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Hypolipidemic Agents / pharmacology*
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Liver / drug effects
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Liver Neoplasms / pathology
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Male
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Myocardial Contraction / drug effects
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Organ Specificity
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Oxygen Consumption / drug effects
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Rats
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Rats, Sprague-Dawley
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Receptors, LDL / metabolism
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Safety
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Thyroid Hormones / pharmacology
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Triglycerides / blood
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Triiodothyronine / metabolism
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Tumor Cells, Cultured
Substances
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Anticholesteremic Agents
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Glyoxylates
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Hypolipidemic Agents
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Receptors, LDL
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Thyroid Hormones
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Triglycerides
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Triiodothyronine
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Cholesterol
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axitrome