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.
Leeson
P D
PD
Smith Kline and French Research Limited, Frythe, Welwyn, Hertfordshire, U.K.
Emmett
J C
JC
Shah
V P
VP
Showell
G A
GA
Novelli
R
R
Prain
H D
HD
Benson
M G
MG
Ellis
D
D
Pearce
N J
NJ
Underwood
A H
AH
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects; D008968:Molecular Conformation; D011817:Rabbits; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D013329:Structure-Activity Relationship; D013963:Thyroid Hormones / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*
D000924:Anticholesteremic Agents; D011988:Receptors, Thyroid Hormone; D013963:Thyroid Hormones