A new class of high affinity thyromimetics containing a phenyl-naphthylene core

Hangeland, Jon J.; Friends, Todd J.; Doweyko, Arthur M.; Mellström, Karin; Sandberg, Johnny; Grynfarb, Marlena; Ryono, Denis E.

doi:10.1016/j.bmcl.2005.06.093

Cited by 13 publications

(3 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It has also been reported that compounds with a phenyl-naphthylene core bind to TR␤ in the sub-nanomolar range and display low to modest selectivity for TR␤. Interestingly, these thyromimetics are the first to display a structure activity relationship that diverges from other thyromimetics that are based on the biaryl ether core found in the thyronine backbone of T 3 (12).…”

Section: Resultsmentioning

confidence: 97%

Design and Characterization of a Thyroid Hormone Receptor α (TRα)-Specific Agonist

Ocasio

Scanlan

2006

ACS Chem. Biol.

View full text Add to dashboard Cite

Thyroid hormone is a classical endocrine signaling molecule that regulates a diverse array of physiological processes ranging from energy metabolism to cardiac performance. The active form of thyroid hormone, 3,5,3'-triiodo- l -thyronine or T 3 , exerts many of its actions through its receptor, the thyroid hormone receptor (TR), of which there are two subtypes for two isoforms: TRalpha 1 , TRalpha 2 , TRbeta 1 , and TRbeta 2 . Although TR isoforms, with the exception of TRbeta 2 , are expressed in all tissues, they display different patterns of expression in different tissues, giving rise to tissue-specific isoform actions. Currently, several TRbeta-selective agonists have been developed; however, TRalpha-selective agonists have remained elusive. Herein, we report the synthesis and biological evaluation of CO23, the first potent thyromimetic with TRalpha-specific effects in vitro and in vivo .

show abstract

Section: Resultsmentioning

confidence: 97%

Design and Characterization of a Thyroid Hormone Receptor α (TRα)-Specific Agonist

Ocasio

Scanlan

2006

ACS Chem. Biol.

View full text Add to dashboard Cite

show abstract

“…Specific DRAGON descriptors and respective regression coefficients employed by the latter model were published (Liu and Gramatica, 2007) allowing us both to recreate the model and apply it to new compounds. We have identified 47 new compounds in our extended dataset tested for their binding with the LBD using the same experimental assay (Carlsson et al ., 2002; Hangeland et al ., 2005; Garcia Collazo et al ., 2006; Koehler et al ., 2006; Garg et al ., 2007; Malm et al ., 2007) that were not part of the datasets used in previous modeling studies. For both models, no correlation between predicted and experimental data for compounds not used in developing the original model was observed (Supplemental Figure 3).…”

Section: Resultsmentioning

confidence: 99%

Prediction of binding affinity and efficacy of thyroid hormone receptor ligands using QSAR and structure-based modeling methods

Politi

Rusyn

Tropsha

2014

Toxicology and Applied Pharmacology

View full text Add to dashboard Cite

The thyroid hormone receptor (THR) is an important member of the nuclear receptor family that can be activated by endocrine disrupting chemicals (EDC). Quantitative Structure-Activity Relationship (QSAR) models have been developed to facilitate the prioritization of THR-mediated EDC for the experimental validation. The largest database of binding affinities available at the time of the study for ligand binding domain (LBD) of THRβ was assembled to generate both continuous and classification QSAR models with an external accuracy of R2=0.55 and CCR=0.76, respectively. In addition, for the first time a QSAR model was developed to predict binding affinities of antagonists inhibiting the interaction of coactivators with the AF-2 domain of THRβ (R2=0.70). Furthermore, molecular docking studies were performed for a set of THRβ ligands (57 agonists and 15 antagonists of LBD, 210 antagonists of the AF-2 domain, supplemented by putative decoys/non-binders) using several THRβ structures retrieved from the Protein Data Bank. We found that two agonist-bound THRβ conformations could effectively discriminate their corresponding ligands from presumed non-binders. Moreover, one of the agonist conformations could discriminate agonists from antagonists. Finally, we have conducted virtual screening of a chemical library compiled by the EPA as part of the Tox21 program to identify potential THRβ-mediated EDCs using both QSAR models and docking. We concluded that the library is unlikely to have any EDC that would bind to the THRβ. Models developed in this study can be employed either to identify environmental chemicals interacting with the THR or, conversely, to eliminate the THR-mediated mechanism of action for chemicals of concern.

show abstract

“…A new set of compounds (Fig. 2— 2 ) reported by Karo Bio took the novel approach of replacing the standard biaryl core with a phenyl-naphthalene core, reported by Hangeland in 2005 [37]. Following this Karo Bio pursued a similar strategy to Bayer in synthesizing thyromimetics with fused ring heterocycles (Fig.…”

Section: Introductionmentioning

confidence: 99%

Quantification of Thyromimetic Sobetirome Concentration in Biological Tissue Samples

Devereaux

Ferrara

Scanlan

2018

Methods in Molecular Biology

View full text Add to dashboard Cite

Thyroid hormone is a principal regulator of essential processes in vertebrate physiology and homeostasis. Synthetic derivatives of thyroid hormone, known as thyromimetics, display desirable therapeutic properties. Thoroughly understanding how thyromimetics distribute throughout the body is crucial for their development and this requires appropriate bioanalytical techniques to quantify drug levels in different tissues. Here, we describe a detailed protocol for the quantification of the thyromimetic sobetirome using liquid chromatography tandem-mass spectrometry (LC-MS/MS).

show abstract

A new class of high affinity thyromimetics containing a phenyl-naphthylene core

Cited by 13 publications

References 24 publications

Design and Characterization of a Thyroid Hormone Receptor α (TRα)-Specific Agonist

Design and Characterization of a Thyroid Hormone Receptor α (TRα)-Specific Agonist

Prediction of binding affinity and efficacy of thyroid hormone receptor ligands using QSAR and structure-based modeling methods

Quantification of Thyromimetic Sobetirome Concentration in Biological Tissue Samples

Contact Info

Product

Resources

About