Synthesis and evaluation of methylsulfonylnitrobenzamides (MSNBAs) as inhibitors of the thyroid hormone receptor–coactivator interaction

We previously identified the methylsulfonylnitrobenzoates (MSNBs) that block the interaction of the thyroid hormone receptor with its obligate transcriptional coactivators and prevent thyroid hormone signaling. As part of our lead optimization work we demonstrated that sulfonylnitrophenylthiazoles (SNPTs), which replace the ester linkage of MSNBs with a thiazole, also inhibited coactivator binding to TR. Here we report that replacement of the ester with an amide (methylsulfonylnitrobenzamides, MSNBA) also provides active TR antagonists.

Graphical abstractWe previously reported a series of methylsulfonylnitrobenzoates (MSNBs) inhibiting the interaction of the thyroid hormone receptor with its coactivators. Here we report the replacement of the ester linkage with the amide linkage, providing active TR antagonism.Figure optionsDownload full-size imageDownload as PowerPoint slide