Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 55, Issue 5, Pages 2301-2310Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm201546m
Keywords
-
Categories
Funding
- NIH [DK58080]
- American Lebanese Syrian Associated Charities (ALSAC)
- St. Jude Children's Research Hospital (SJCRH)
Ask authors/readers for more resources
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 (beta-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).
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available