Selective activation of thyroid hormone signaling pathways by GC-1: a new approach to controlling cholesterol and body weight

• Published in: Trends in endocrinology and metabolism 2004-05, Vol.15 (4), p.154-157
• Main Authors: Baxter, John D., Webb, Paul, Grover, Gary, Scanlan, Tom S.
• Format: Article
• Language: English
• Subjects: Acetates - pharmacokinetics; Acetates - pharmacology; Animals; Anticholesteremic Agents - pharmacology; Biological and medical sciences; Body Weight - drug effects; Cholesterol - blood; Fundamental and applied biological sciences. Psychology; Hormones. Regulation; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Lipoproteins - blood; Phenols - pharmacokinetics; Phenols - pharmacology; Signal Transduction - drug effects; Thyroid Hormone Receptors alpha - drug effects; Thyroid Hormone Receptors beta - drug effects; Thyroid Hormones - adverse effects; Thyroid Hormones - pharmacology; Thyroid Hormones - physiology; Thyroid. Parathyroid. Ultimobranchial body; Vertebrates: endocrinology; Weight Loss - drug effects
• ISSN: 1043-2760; 1879-3061
• DOI: 10.1016/j.tem.2004.03.008

The current report describes progress in development of a selective thyroid hormone receptor modulator, GC-1. This compound binds selectively to the β-isoform of the thyroid hormone receptor, and its uptake into the heart is relatively low. Studies in rats, mice and monkeys show that GC-1 lowers cholesterol with 600- to 1400-fold more potency and approximately two- to threefold more efficacy than atorvastatin, a compound that blocks HMG-CoA reductase. GC-1 also decreases plasma levels of triglyceride and lipoprotein (a), and induces loss of fat. These effects can be observed under conditions where there is either no or minimal effect on heart rate, and no detectable loss of muscle. Although more study is required, compounds of this class deserve further investigation for treating lipid disorders and obesity.