Synthesis and Evaluation of Sulfonylnitrophenylthiazoles (SNPTs) as Thyroid Hormone Receptor–Coactivator Interaction Inhibitors

Abstract

We previously identified a series of methylsulfonylnitrobenzoates (MSNB's) that block the interaction of the thyroid hormone receptor with its coactivators. MSNB's inhibits coactivator binding through irreversibly modifying cysteine 298 of thyroid hormone receptor (TR). Although MSNB's 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 (SNPT's). An array of SNPT's 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 SNPT's shown to be selective for TR relative to other nuclear hormone receptor (NR).

In silico modelling of prostacyclin and other lipid mediators to nuclear receptors reveal novel thyroid hormone receptor antagonist properties

“…Here we show that full dilation is achieved at 3 × 10 −7 mol/L T3, which was significantly reduced by incubation with the TR antagonist MLS. While MLS cannot differentiate between TR␣ and TR␤ [29], without further study we can only conclude that T3 induces vasodilation in rat mesenteric arteries that is TR␣ and TR␤ mediated and not dependent on nitric oxide synthase.…”

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

“…The affinity data were reported as IC 50 values determined from the radioligand binding assay as described by Ye(Ye et al ., 2003). For the AF-2 domain, 210 ligands were found; however, only 181 had well-defined IC 50 values(Arnold et al ., 2007b; Hwang et al ., 2009; Hwang et al ., 2012) (see Table 2). The IC 50 values associated with inhibition of co-regulatory peptide SRC2-2 binding to THRβ were determined using fluorescence polarization(Arnold et al ., 2007b; Hwang et al ., 2009; Hwang et al ., 2012).…”

“…Recently, a series of THR antagonists have been identified that inhibit THR-coactivator interaction by binding to the AF-2 domain (Arnold et al ., 2005; Arnold et al ., 2006; Arnold et al ., 2007a; Arnold et al ., 2007b; Estebanez-Perpina et al ., 2007a; Hwang et al ., 2009; Hwang et al ., 2011; Hwang et al ., 2012; Hwang et al ., 2013). These compounds may be useful to treat metabolic disorders and hyperthyroidism without affecting thyroid hormone levels; however additional studies revealed significant dose-related cardiotoxicity, suspected to arise from ion-channel inhibition(Arnold et al ., 2005; Arnold et al ., 2006; Arnold et al ., 2007a; Arnold et al ., 2007b; Estebanez-Perpina et al ., 2007a; Hwang et al ., 2009; Hwang et al ., 2011; Hwang et al ., 2012; Hwang et al ., 2013).…”

“…These compounds may be useful to treat metabolic disorders and hyperthyroidism without affecting thyroid hormone levels; however additional studies revealed significant dose-related cardiotoxicity, suspected to arise from ion-channel inhibition(Arnold et al ., 2005; Arnold et al ., 2006; Arnold et al ., 2007a; Arnold et al ., 2007b; Estebanez-Perpina et al ., 2007a; Hwang et al ., 2009; Hwang et al ., 2011; Hwang et al ., 2012; Hwang et al ., 2013). …”

Agonist Ligands Mediate the Transcriptional Response of Nuclear Receptor Heterodimers through Distinct Stoichiometric Assemblies with Coactivators

“…However, the recruitment of a second coactivator to RAR(agonist): RXR(agonist) is restricted through long-range, agonist-induced conformational changes that disrupt the RXR coactivatorbinding site (53). Third, targeting coactivators for therapy is of growing interest (54,55), thus requiring a detailed knowledge of such binding events. These coactivators display different binding specificities for the receptors both independently (56) and within the heterodimer (15), thus, it is likely that the specific interactions between each SRC1 molecule and the two binding sites on CAR:RXR are distinct.…”