Selective Thyromimetics. Cardiac-Sparing Thyroid Hormone Analogues Containing 3'-Arylmethyl Substituents

Article abstract of DOI:10.1021/jm00122a009

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 α-amino group to give a propionic acid results in loss of selective thyromimetic activity.