Recent Advances in the Development of Agonists Selective for β1-Type Thyroid Hormone Receptor

Abstract

This mini-review will provide an overview on the recent design principles and structure-activity-relationship of beta-selective thyroid hormone receptor (TR) agonists. The prospects for the treatment of metabolic diseases as dyslipidemia with TRbeta-selective ligands are considerable enough so as to avoid cardiovascular acceleration mediated through TRalpha.

3D-QSAR and molecular docking studies of selective agonists for the thyroid hormone receptor β

“…In addition, the two oxygen atoms of the terminal of B ring form three hydrogen bonds to Asn 233, Arg 282 and Arg 320 as hydrogen-bond acceptors. The results are in good agreement with the experimental conclusion of Malm's work [17].…”

“…TRa was reported to mediate the effects of thyroid hormones on the heart, and in particular on the heart rate and rhythm, while most actions of the hormones on the liver and other tissues are mediated more through the b-forms of receptor [11,12]. Up to now, there are many reported thyroid ligands [13][14][15][16][17]. The group of Malm synthesized several series of selective ligands for TRb [18][19][20][21][22][23][24], based on the structures of endogenous thyroid receptor hormones 3,5,3 0 ,5 0 -tetraiodo-L-thyronine (T4) and 3,5,3 0 -triiodo-L-thyronine (T3).…”

Selective thyroid hormone receptor modulators

“…Differential ribonucleic acid (RNA) processing results in the formation of several isoforms from each gene. [8] The TR α1, TR β1 and TR β2 isoforms bind THs and act as ligand-regulated transcription factors. Their predominant distribution and role is depicted in Table 1.…”

Thyroid Hormones and Thyromimetics

“…TRa 1 is most abundant in the heart and most effects of L-T 3 on the heart are mediated through TRa 1 , while the majority of lipid-lowering actions in the liver are mediated through TRb 1 [48, [235][236][237][238]. The prospect for the treatment of metabolic diseases such as hypercholesterolemia with TRb 1 -selective ligands is therefore considerable as cardiovascular acceleration mediated through TRa 1 thus can be avoided [239][240][241]. Consequently, the availability of X-ray structures of TRb 1 -selective thyromimetics in complex with LBD X-ray structures is required when designing isoform-selective thyromimetics.…”