Thyroid hormone analogues

Structure—Activity Relationships. In spite of the considerable synthetic and bioassay effort involved in estabhshing the thyromimetic potency of thyroid-hormone analogues, more than 100 compounds have been studied (Table 2). The main stmctural requirements for thyromimetic activity can be summarized as follows (6,12—16). 

A large number of thyroid hormone analogues have been tested for this effect (6). Among others, i-T (3) and 3,3 -T2 (5) and their propionic acid side-chain analogues decrease oxygen consumption at molar ratios of 50—200 1 of T. Nevertheless, no potent or clinically usehil peripheral antagonists have been found. 

Within a programme aimed at the development of thyroid hormone analogues as potentially useful plasma cholesterol-lowering agents, the pyrida-zinone derivative SK F L-94901 (98) has been prepared and investigated in the U.K. [419-422]. Whereas naturally occurring thyroid hormones cannot be employed for this purpose because of their undesirable effect on heart rate, (98) has been found to represent a potent thyromimetic which retains hepatic activity but lacks cardiac activity. Structural modifications and QSAR studies have been carried out [422]. 

Chiellini, G. Nguyen, N.-H. Apriletti, J. W. Baxter, J. D. Scanlan, T. S. Synthesis and biological activity of novel thyroid hormone analogues 5 -aryl substituted GC-1 derivatives. Bioorg. Med. Chem. 2002, 10, 333—346. 

Mousa SA, O Connor LJ, Bergh JJ, et al, The proangiogenic action of thyroid hormone analogue GC-I is initiated at an integrin, J Cardiovasc Pharmacol 2005 46 356-360,... 

K. W. Mahaffey, T.E. Raya, G.D. Pennock, E. Morkin and S. Goldman, Left ventricular performance and remodeling in rabbits after myocardial infarction effects of a thyroid hormone analogue, Circulation 91(3), 794-801 (1995). 

We next apphed the method of MaNP acid 3, which is very effective for enantior-esolving racemic alcohols and also for determining the absolute configuration of chiral alcohols by the H NMR anisotropy method as described above. We explain here the apphcation of the MaNP acid method to the chiral thyroid hormone analogue KAT-2003 (-i-)-9 to determine its absolute configuration. 

Leeson, P.D., Ellis, D., Emmett, J.C., Shah, V.P., Showell. G.A., and Underwood, A.H., Thyroid hormone analogues. Synthesis of 3 -substituted 3,5-diiodo-L-thyronines and quantitative structure-activity studies of in vivo thyromimetic activities in rat liver and heart, J. Med. Chem., 31, 37, 1988. 

The search for thyroid hormone analogues was prompted by the desire to establish SARs for the hormone and by the need for a safe, specific antagonist able to block thyroid action without delay at a peripheral site. The reader will recall that TPO inhibitors, such as PTU, do not affect the extensive amount of hormone stored in thyroidal thyroglobulin. 

Leeson PD, Ellis D, Emmett JC, et al. Thyroid hormone analogues. Synthesis of 3 -substituted... 

Kollman PA, Murray WJ, Nuss ME, et al. Molecular orbital studies of thyroid hormone analogues. J Am Chem Soc 1973 95 8518-8525. 

Eprotirome (KB2115) is a thyroid hormone analogue that has modestly higher affinity for the triiodothyronine receptor p isoform (and mediates the lipid-lowering actions of thyroid hormone) compared with its affinity for the triiodothyronine receptor a isoform in the heart. 

Burridge, and C. C. F. Blake,/. Am. Chem. Soc., 104, 6424 (1982). Molecular Mechanics Simulation of Protein-Ligand Interactions Binding of Thyroid Hormone Analogues to Prealbumin. 

Nishimura T, Taji H, Harada N. Absolute configuration of the thyroid hormone analogue KAT-2003 as determined by the H NMR anisotropy method with a novel chiral auxiliary, MaNP acid. C/ >a/fty 2004 16 13-21. 

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