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Targeting thyroid hormone receptor-beta agonists to the liver reduces cholesterol and triglycerides and improves the

Mark D Erion1, Edward E Cable, Bruce R Ito

  • 1Metabasis Therapeutics, Inc., 11119 North Torrey Pines Road, La Jolla, CA 92037, USA. erion@mbasis.com

Proceedings of the National Academy of Sciences of the United States of America
|September 20, 2007
PubMed

Insights

A novel liver-targeted thyroid hormone receptor (TR) agonist prodrug, MB07811, effectively lowers cholesterol and triglycerides. This approach offers a potential therapeutic strategy for metabolic disorders with an improved safety profile, overcoming previous limitations of TR agonists.

Area of Science:

  • Endocrinology and Metabolism
  • Pharmacology and Drug Discovery
  • Molecular Biology

Background:

  • Thyroid hormone receptor (TR) agonists show promise for lipid-lowering and anti-obesity effects but are limited by cardiac and thyroid hormone axis (THA) side effects.
  • Existing TR agonists, even selective TRbeta isoforms, fail to lower lipids without suppressing the THA, hindering therapeutic application.
  • Developing TR agonists with improved therapeutic indices requires strategies to enhance liver-specific activation and minimize extrahepatic effects.

Purpose of the Study:

  • To describe a novel cytochrome P450-activated prodrug designed for enhanced liver targeting of TR agonists.
  • To evaluate the pharmacokinetic profile and therapeutic efficacy of this liver-targeted prodrug (MB07811) in preclinical models.
  • To assess the safety profile, particularly cardiac and THA effects, of the liver-targeted TR agonist compared to non-targeted agents.

Main Methods:

  • Synthesis and characterization of a phosphonate-containing TR agonist prodrug, MB07811, and its active metabolite, MB07344.
  • Pharmacokinetic studies in rats to determine hepatic extraction, metabolism, and elimination of MB07811.
  • Comparative gene expression analysis in liver and extrahepatic tissues following treatment with MB07811, T(3), and KB-141.
  • Assessment of lipid-lowering, anti-obesity, glycemic, cardiac, and THA effects in normal rats and diet-induced obese mice.

Main Results:

  • MB07811 undergoes first-pass hepatic metabolism to generate the active TR agonist MB07344, which exhibits poor distribution and rapid biliary elimination.
  • Liver-targeted MB07811 demonstrated significant reductions in cholesterol and triglycerides in diet-induced obese mice without affecting body weight, glycemia, or the THA.
  • MB07811 showed improved cardiac sparing compared to non-liver-targeted TR agonists in preclinical models.

Conclusions:

  • Targeting TR agonists to the liver via prodrug activation represents a promising strategy to achieve therapeutic lipid-lowering effects.
  • MB07811 demonstrates a favorable therapeutic index, effectively reducing cholesterol and triglycerides with an acceptable safety profile.
  • This liver-targeting approach overcomes key limitations of previous TR agonists, paving the way for potential human therapies for dyslipidemia and obesity.

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