Abstract
We previously identified a series of methylsulfonylnitrobenzoates (MSNBs) that block the interaction of the thyroid hormone receptor with its coactivators. MSNBs inhibit coactivator binding through irreversible modification of cysteine 298 of the thyroid hormone receptor (TR). Although MSNBs have better pharmacological features than our first generation inhibitors (β-aminoketones), they contain a potentially unstable ester linkage. Here we report the bioisosteric replacement of the ester linkage with a thiazole moiety, yielding sulfonylnitrophenylthiazoles (SNPTs). An array of SNPTs representing optimal side chains from the MSNB series was constructed using parallel chemistry and evaluated to test their antagonism of the TR-coactivator interaction. Selected active compounds were evaluated in secondary confirmatory assays including regulation of thyroid response element driven transcription in reporter constructs and native genes. In addition the selected SNPTs were shown to be selective for TR relative to other nuclear hormone receptors (NRs).
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Genes, Reporter
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Hep G2 Cells
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Humans
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Matrix Metalloproteinase 11 / genetics
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Matrix Metalloproteinase 11 / metabolism
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Models, Molecular
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Nitro Compounds / chemical synthesis*
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Nitro Compounds / chemistry
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Nitro Compounds / pharmacology
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Nuclear Receptor Coactivators / antagonists & inhibitors*
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Nuclear Receptor Coactivators / metabolism
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Phosphoenolpyruvate Carboxykinase (ATP) / genetics
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Phosphoenolpyruvate Carboxykinase (ATP) / metabolism
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Receptors, Thyroid Hormone / antagonists & inhibitors*
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Receptors, Thyroid Hormone / metabolism
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Response Elements
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Structure-Activity Relationship
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Sulfones / chemical synthesis*
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Sulfones / chemistry
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Sulfones / pharmacology
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Thiazoles / chemical synthesis*
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Thiazoles / chemistry
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Thiazoles / pharmacology
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Transcription, Genetic / drug effects
Substances
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Nitro Compounds
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Nuclear Receptor Coactivators
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Receptors, Thyroid Hormone
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Sulfones
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Thiazoles
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MMP11 protein, human
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Matrix Metalloproteinase 11
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Phosphoenolpyruvate Carboxykinase (ATP)