Discovery of a novel series of 6-azauracil-based thyroid hormone receptor ligands: potent, TRβ subtype-selective thyromimetics

Dow, Robert L.; Schneider, Steven R.; Paight, Ernest S.; Hank, Richard F.; Chiang, Phoebe; Cornelius, Peter; Lee, Eun-Sun; Newsome, William; Swick, Andrew G.; Spitzer, Josephine; Hargrove, Diane M.; Patterson, Terrell A.; Pandit, J.; Chrunyk, Boris A.; LeMotte, Peter K.; Danley, Dennis E.; Rosner, Michele H.; Ammirati, Mark; Simons, Samuel P.; Schulte, Gayle K.; Tate, Bonnie F.; DaSilva-Jardine, Paul

doi:10.1016/s0960-894x(02)00947-2

Cited by 65 publications

(59 citation statements)

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“…Resolution of the three-dimensional structure of TR ligand binding domain has allowed the development of detailed structure-activity relationships for TR agonists and antagonists (Green et al, 1988;Renaud et al, 1995;Ribeiro et al, 1998;Yen, 2001;Dow et al, 2003;Hangeland et al, 2004). TRs have two known subtypes, TR␣ and TR␤, that are generated from different genes (Forrest and Vennström, 2000;Yen, 2001), with TR␣ regulating heart rate and most of the metabolic rate effects of T 3 and with TR␤ mediating cholesterol and TSH suppression Wikström et al, 1998;Grover et al, 2003).…”

mentioning

confidence: 99%

“…TRs have two known subtypes, TR␣ and TR␤, that are generated from different genes (Forrest and Vennström, 2000;Yen, 2001), with TR␣ regulating heart rate and most of the metabolic rate effects of T 3 and with TR␤ mediating cholesterol and TSH suppression Wikström et al, 1998;Grover et al, 2003). Recent studies show that development of TR subtype-selective agonists is possible, and these are useful tools for dissecting TR function (Chiellini et al, 1998;Trost et al, 2000;Scanlan et al, 2001;Dow et al, 2003). Structure-activity relationships have also been generated with the purpose of developing TR antagonists, although few are useful in vivo (Carlsson et al, 2002;Malm, 2004a).…”

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confidence: 99%

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Pharmacological Profile of the Thyroid Hormone Receptor Antagonist NH3 in Rats

Grover¹,

Dunn²,

Nguyen³

et al. 2007

J Pharmacol Exp Ther

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NH3 is a thyroid hormone receptor (TR) antagonist that inhibits binding of thyroid hormones to their receptor and that inhibits cofactor recruitment. It was active in a tadpole tail resorption assay, with partial agonist activity at high concentrations. We determined the effect of NH3 on the cholesterol-lowering, thyroid stimulating hormone (TSH)-lowering, and tachycardic action of thyroid hormone (T 3 ) in rats. Cholesterol-fed, euthyroid rats were treated for 7 days with NH3, and a dose response (46.2-27,700 nmol/kg/day) was determined. We also determined the effect of two doses of T 3 on the NH3 dose-response curve. NH3 decreased heart rate modestly starting at 46.2 nmol/kg/day, but the effect was lost at Ͼ2920 nmol/kg/day. At 27,700 nmol/kg/day, tachycardia was seen, suggesting partial agonist activity. NH3 increased plasma cholesterol to a maximum of 27% at 462 nmol/kg/day. At higher doses, cholesterol was reduced, suggesting partial agonist activity. Plasma TSH was increased from 46.2 to 462 nmol/kg/day NH3, but at higher doses, this effect was lost, and partial agonist effects were apparent. T 3 at 15.4 and 46.2 nmol/kg/day increased heart rate, reduced cholesterol, and reduced plasma TSH. NH3 inhibited the cholesterol-lowering, TSH-lowering and tachycardic effects of 15.4 nmol/kg/day T 3 , but much of the effect was lost at Ͼ924 nmol/kg/day doses. NH3 had no effect on the cholesterollowering action of 46.2 nmol/kg/day T 3 , but it inhibited the tachycardic and TSH suppressant effects up to the 924 nmol/ kg/day dose. Single doses of 462 and 27,700 nmol/kg caused no TR inhibitory effects. In conclusion, NH3 has TR antagonist properties on T 3 -responsive parameters, but it has partial agonist properties at higher doses.

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confidence: 99%

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confidence: 99%

Pharmacological Profile of the Thyroid Hormone Receptor Antagonist NH3 in Rats

Grover¹,

Dunn²,

Nguyen³

et al. 2007

J Pharmacol Exp Ther

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“…Due to the significance and detail of these original works, crystal structure work grew rapidly and a number of novel thyromimetics bound to TRb 1 [175][176][177][178][179][180][181] and TRa 1 [177,181] were later reported.…”

Section: Thyroid Hormone Receptor Agonist Structuresmentioning

confidence: 99%

“…Through screening for TRs of their own compound collection, Pfizer subsequently discovered highly novel and surprisingly potent R 1 -position 6-azauracil thyromimetics that bound to TRb 1 with submicromolar potencies and with modest selectivity versus TRb 1 [176]. The most potent analog 18 (Fig.…”

Section: Variation Of the R 1 -Positionmentioning

confidence: 99%

“…This is an important finding that emphasizes the potential of GC-24 as a selective therapeutic agent. Compounds Based on R 1 -Azauracil Novel substitution with heterocyclic rings at the R 1 -position was accomplished through the 6-azauracil-based thyromimetics [176], which is reviewed in the section "Heterocyclic rings." Continued SAR work on the R increase in TRb 1 selectivity was seen when the R 0 3 -position was substituted with various R 0 3 -carboxamides and sulfonamides.…”

Section: Ring-closure Of the R 1 And R 2 -Positionsmentioning

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Thyroid Hormones and Thyromimetics

Malm

Grover

2010

Burger's Medicinal Chemistry and Drug Discovery

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Recent Trends in Structure‐Based Drug Design and Energetics

Andricopulo

Güido

Trivella

et al. 2010

Burger's Medicinal Chemistry and Drug Discovery

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The integration of cheminformatics tools, thermodynamic data, and structural information play a major role in the drug discovery process. Altogether, these methods can describe the molecular forces that govern the affinity and selectivity of bioactive molecules for their macromolecular targets. By being able to uncover the relationships between structure and energetics when using high‐resolution structural information and modern biophysical methods, one can fulfill the challenge of correctly interpreting drug–macromolecular interactions. These interactions are prone to be unveiled and scrutinized when structure‐based drug design is applied to a known three‐dimensional (3D) structure of a given protein. If fully integrated with structure‐based ligand design in an iterative way, computational methods can be of invaluable help to describe the ligand–target (cocomplex) formation. Structure‐based virtual screening can be used to rapid cherry‐pick the best candidates from a large pool of compounds in a chemical library after docking into the active sites of 3D protein structures. To pursue this, the quantification of favorable and unfavorable interactions requires knowledge of the thermodynamics of the interactions. Docking algorithms and molecular dynamics simulations can be used to predict binding energies for positioning ligands in target binding sites, but they only provide information regarded to the prediction of the change in the Gibbs free energy change, which hampers the thoroughly dissection of all other very important thermodynamic parameters—enthalpy, entropy, and heat capacity change. The major goal of this chapter is to show the integration of structure‐based drug design with the energetic. Microcalorimetric measurement of the drug–macromolecular interaction is an effective way to enhance the power, the medicinal chemists have on hand, to pursue a knowledge‐based approach toward the description of all of the noncovalent bond terms that take place in the cocomplex formation.

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Discovery of a novel series of 6-azauracil-based thyroid hormone receptor ligands: potent, TRβ subtype-selective thyromimetics

Cited by 65 publications

References 9 publications

Pharmacological Profile of the Thyroid Hormone Receptor Antagonist NH3 in Rats

Pharmacological Profile of the Thyroid Hormone Receptor Antagonist NH3 in Rats

Thyroid Hormones and Thyromimetics

Recent Trends in Structure‐Based Drug Design and Energetics

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