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

Jong Yeon Hwang; Ramy R. Attia; Angela K. Carrillo; Michele C. Connelly; R. Kiplin Guy

doi:10.1016/j.bmcl.2012.12.055

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

Jong Yeon Hwang, Ramy R. Attia, Angela K. Carrillo, Michele C. Connelly, R. Kiplin Guy

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	1891-1895
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	23
Issue number	6
DOIs	https://doi.org/10.1016/j.bmcl.2012.12.055
State	Published - Mar 15 2013

Bibliographical note

Funding Information:
This work was supported by NIH/NIAID (Grant Al075517 , DK58080 ), the American Lebanese Syrian Associated Charities (ALSAC), and St. Jude Children’s Research Hospital.

Keywords

Coactivator
Inhibitor
Protein interaction
Thyroid

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmcl.2012.12.055

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title = "Synthesis and evaluation of methylsulfonylnitrobenzamides (MSNBAs) as inhibitors of the thyroid hormone receptor-coactivator interaction",

abstract = "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.",

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note = "Funding Information: This work was supported by NIH/NIAID (Grant Al075517 , DK58080 ), the American Lebanese Syrian Associated Charities (ALSAC), and St. Jude Children{\textquoteright}s Research Hospital. ",

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AU - Hwang, Jong Yeon

AU - Attia, Ramy R.

AU - Carrillo, Angela K.

AU - Connelly, Michele C.

AU - Guy, R. Kiplin

N1 - Funding Information: This work was supported by NIH/NIAID (Grant Al075517 , DK58080 ), the American Lebanese Syrian Associated Charities (ALSAC), and St. Jude Children’s Research Hospital.

PY - 2013/3/15

Y1 - 2013/3/15

N2 - 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.

AB - 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.

KW - Coactivator

KW - Inhibitor

KW - Protein interaction

KW - Thyroid

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JO - Bioorganic and Medicinal Chemistry Letters

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IS - 6

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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