Selective thyromimetics. Cardiac-sparing thyroid hormone analogues containing 3'-arylmethyl substituents

J Med Chem. 1989 Feb;32(2):320-36. doi: 10.1021/jm00122a009.

Abstract

Introduction of specific arylmethyl groups at the 3'-position of the thyroid hormone 3,3',5-triiodo-L-thyronine (T3), and its known hormonally active derivatives, gives liver-selective, cardiac-sparing thyromimetics, with potential utility as plasma cholesterol lowering agents. Selectivity-conferring 3'-substituents include substituted benzyl, e.g. p-hydroxybenzyl, and heterocyclic methyl, e.g. 2-oxo-1,2-dihydropyrid-5-ylmethyl and 6-oxo-1,6-dihydropyridazin-3-ylmethyl. Correlations between in vivo and in vitro receptor binding affinities show that liver/heart selectivity does not depend on receptor recognition but on penetration or access to receptors in vivo. QSAR studies of the binding data of a series of 20 3'-arylmethyl T3 analogues show that electronegative groups at the para position increase both receptor binding and selectivity in vivo. However, increasing 3'-arylmethyl hydrophobicity increases receptor binding but reduces selectivity. Substitution at ortho and meta positions reduces both binding and selectivity. Replacement of the 3,5-iodo groups by halogen or methyl maintains selectivity, with 3,5-dibromo analogues in particular having increased potency combined with oral bioavailability. Diphenyl thioether derivatives also have improved potency but are less orally active. At the 1-position, the D enantiomer retains selectivity, but removal of the alpha-amino group to give a propionic acid results in loss of selective thyromimetic activity.

MeSH terms

  • Animals
  • Anticholesteremic Agents / pharmacology
  • Heart / drug effects*
  • In Vitro Techniques
  • Liver / drug effects
  • Molecular Conformation
  • Rabbits
  • Receptors, Thyroid Hormone / metabolism
  • Structure-Activity Relationship
  • Thyroid Hormones / chemical synthesis
  • Thyroid Hormones / pharmacokinetics
  • Thyroid Hormones / pharmacology*

Substances

  • Anticholesteremic Agents
  • Receptors, Thyroid Hormone
  • Thyroid Hormones