Thyroid Receptor Ligands. 1. Agonist Ligands Selective for the Thyroid Receptor β₁

Abstract

Endogenous thyroid receptor hormones 3,5,3',5'-tetraiodo-l-thyronine (T(4), 1) and 3,5,3'-triiodo-l-thyronine (T(3), 2) exert a significant effects on growth, development, and homeostasis in mammals. They regulate important genes in intestinal, skeletal, and cardiac muscles, the liver, and the central nervous system, influence overall metabolic rate, cholesterol and triglyceride levels, and heart rate, and affect mood and overall sense of well being. The literature suggests many or most effects of thyroid hormones on the heart, in particular on the heart rate and rhythm, are mediated through the TRalpha(1) isoform, while most actions of the hormones on the liver and other tissues are mediated more through the TRbeta(1) isoform of the receptor. Some effects of thyroid hormones may be therapeutically useful in nonthyroid disorders if adverse effects can be minimized or eliminated. These potentially useful features include weight reduction for the treatment of obesity, cholesterol lowering for treating hyperlipidemia, amelioration of depression, and stimulation of bone formation in osteoporosis. Prior attempts to utilize thyroid hormones pharmacologically to treat these disorders have been limited by manifestations of hyperthyroidism and, in particular, cardiovascular toxicity. Consequently, development of thyroid hormone receptor agonists that are selective for the beta-isoform could lead to safe therapies for these common disorders while avoiding cardiotoxicity. We describe here the synthesis and evaluation of a series of novel TR ligands, which are selective for TRbeta(1) over TRalpha(1). These ligands could potentially be useful for treatment of various disorders as outlined above. From a series of homologous R(1)-substituted carboxylic acid derivatives, increasing chain length was found to have a profound effect on affinity and selectivity in a radioreceptor binding assay for the human thyroid hormone receptors alpha(1) and beta(1) (TRalpha(1) and TRbeta(2)) as well as a reporter cell assay employing CHOK1-cells (Chinese hamster ovary cells) stably transfected with hTRalpha(1) or hTRbeta(1) and an alkaline phosphatase reporter-gene downstream thyroid response element (TRAFalpha(1) and TRAFbeta(1)). Affinity increases in the order formic, acetic, and propionic acid, while beta-selectivity is highest when the R(1) position is substituted with acetic acid. Within this series 3,5-dibromo-4-[(4-hydroxy-3-isopropylphenoxy)phenyl]acetic acid (11a) and 3,5-dichloro-4-[(4-hydroxy-3-isopropylphenoxy)phenyl]acetic acid (15) were found to reveal the most promising in vitro data based on isoform selectivity and were selected for further in vivo studies. The effect of 2, 11a, and 15 in a cholesterol-fed rat model was monitored including potencies for heart rate (ED(15)), cholesterol (ED(50)), and TSH (ED(50)). Potency for tachycardia was significantly reduced for the TRbeta selective compounds 11a and 15 compared with 2, while both 11a and 15 retained the cholesterol-lowering potency of 2. This left an approximately 10-fold ...

Gaining ligand selectivity in thyroid hormone receptors via entropy

“…The TR ligand-binding cavity (LBC), like that of other NRs, lies in the core of the C-terminal ligand-binding domain (LBD) (6). TR␤-selective binding of GC-1 (Ϸ5-fold) and KB141 (Ϸ10-fold) is dependent on a single TR subtype-specific residue in the LBC, TR␤Asn-331 and TR␣Ser-277 (7,8). These lie in a hydrophilic region of the LBC that contacts charged groups of the T 3 amino propionate group, and pocket swap mutations that reverse the identity of these residues also reverse TR preference for GC-1 and KB141.…”

“…These lie in a hydrophilic region of the LBC that contacts charged groups of the T 3 amino propionate group, and pocket swap mutations that reverse the identity of these residues also reverse TR preference for GC-1 and KB141. X-ray structural analysis indicates that TR␤Asn-331 repositions Arg-282 relative to its TR␣ equivalent (Arg-228), and this facilitates hydrogen bond formation between the Arg-282 side chain and the GC-1 or KB141 carboxylate group (7)(8)(9). TR␤-selective binding of GC-24 (Ϸ40-fold) is partly dependent on Asn-331␤ but involves another mechanism (10); ligand occupies the LBC and conserved hydrophobic regions of helices (H) 3 and 11 open to form an extension to the LBC that accommodates a bulky GC-24 phenyl group.…”

Resistance to diet-induced obesity in mice globally overexpressing OGH/GPB5

“…The two major subtypes of the thyroid hormone receptors that mediate these responses, TR␣ and TR␤, are the products of different genes and are also differentially processed to each yield two isoforms. It has been argued that modulation of heart rate and rhythm is mediated predominantly by activation of TR␣ 1 (2)(3)(4), and as a result, recent pharmaceutical research efforts have focused on developing specific TR␤ 1 agonists (5)(6)(7)(8).…”

Small-Molecule Triggers of Tadpole Metamorphosis

“…Point of VIEW www.acschemicalbiology.org VOL.1 NO.9 • ACS CHEMICAL BIOLOGY compound 3 (13) and TR␤ bound to T 3 (1) (14) is shown (Figure 2).…”

“…In contrast, GC-1 (12) and compound 3 (13) are selective agonists of TR␤ because they bind substantially more tightly to this protein subtype. Several available X-ray structures of TRs bound to ligands (13)(14)(15)(16) show that the selective binding of GC-1 (2) and compound 3 to TR␤ appears to result from participation of the carboxylate moiety in a hydrogen bonding network that includes the TR␤ Asn331 residue.…”