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The thyroid hormone mimetic compound KB2115 lowers plasma LDL cholesterol and stimulates bile acid synthesis without cardiac effects in humans.

Abstract
Atherosclerotic cardiovascular disease is a major problem despite the availability of drugs that influence major risk factors. New treatments are needed, and there is growing interest in therapies that may have multiple actions. Thyroid hormone modulates several cardiovascular risk factors and delays atherosclerosis progression in humans. However, use of thyroid hormone is limited by side effects, especially in the heart. To overcome this limitation, pharmacologically selective thyromimetics that mimic metabolic effects of thyroid hormone and bypass side effects are under development. In animal models, such thyromimetics have been shown to stimulate cholesterol elimination through LDL and HDL pathways and decrease body weight without eliciting side effects. We report here studies on a selective thyromimetic [KB2115; (3-[[3,5-dibromo-4-[4-hydroxy-3-(1-methylethyl)-phenoxy]-phenyl]-amino]-3-oxopropanoic acid)] in humans. In moderately overweight and hypercholesterolemic subjects KB2115 was found to be safe and well tolerated and elicited up to a 40% lowering of total and LDL cholesterol after 14 days of treatment. Bile acid synthesis was stimulated without evidence of increased cholesterol production, indicating that KB2115 induced net cholesterol excretion. KB2115 did not provoke detectable effects on the heart, suggesting that the pharmacological selectivity observed in animal models translates to humans. Thus, selective thyromimetics deserve further study as agents to treat dyslipidemia and other risk factors for atherosclerosis.
AuthorsAnders Berkenstam, Jens Kristensen, Karin Mellström, Bo Carlsson, Johan Malm, Stefan Rehnmark, Neeraj Garg, Carl Magnus Andersson, Mats Rudling, Folke Sjöberg, Bo Angelin, John D Baxter
JournalProceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 105 Issue 2 Pg. 663-7 (Jan 15 2008) ISSN: 1091-6490 [Electronic] United States
PMID18160532 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • 3-((3,5-dibromo-4-(4-hydroxy-3-(1-methylethyl)phenoxy)phenyl)amino)-3-oxopropanoic acid
  • Anilides
  • Bile Acids and Salts
  • Cholesterol, LDL
  • Placebos
  • Thiazolidinediones
  • Thyroid Hormones
Topics
  • Adolescent
  • Adult
  • Anilides (chemistry, pharmacology)
  • Bile Acids and Salts (metabolism)
  • Cholesterol, LDL (metabolism)
  • Double-Blind Method
  • Female
  • Heart (drug effects)
  • Humans
  • Lipid Metabolism
  • Male
  • Middle Aged
  • Placebos
  • Risk Factors
  • Thiazolidinediones (pharmacology)
  • Thyroid Gland (drug effects)
  • Thyroid Hormones (metabolism)

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