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

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.

3'-Acetyl-3,5-diiodo-L-thyronine: a novel highly active thyromimetic with low receptor affinity.

The 4'-phenolic hydroxyl group of thyroid hormones plays an important role in receptor binding, and it has been suggested that the interaction of this hydroxyl group with the receptor involves hydrogen bonding via donation of the acidic hydrogen in a trans disposition to the 3'-substituent of the hormones. In order to test this hypothesis we have synthesised, and measured the hepatic receptor affinity and thyromimetic activity of 3'-acetyl-3,5-diiodo-L-thyronine (3'-Ac-T2), a compound in which the formation of such a receptor-phenol hydrogen bond is precluded by the presence of a strong intramolecular hydrogen bond between the 3'-acetyl- and 4'-hydroxyl groups. In confirmation of the hypothesis, 3'-Ac-T2 has a low affinity (0.5% of that of 3,5,3'-triiodo-L-thyronine, T3) for the T3-receptor in isolated rat hepatic nuclei. By contrast the thyromimetic activity (assessed by its ability to induce rat hepatic glycerol-3-phosphate dehydrogenase and increase the qO2 of liver slices) was roughly equal to that of T3. This apparent discrepancy was resolved when it was found that the capacity of 3'-Ac-T2 to occupy hepatic receptors after in vivo administration, was about 100 times greater than predicted from its in vitro affinity. The reason for this difference between in vivo and in vitro nuclear binding is unknown at the present time.