Rational Design and Synthesis of a Novel Thyroid Hormone Antagonist That Blocks Coactivator Recruitment

• Published in: Journal of medicinal chemistry 2002-07, Vol.45 (15), p.3310-3320
• Main Authors: Nguyen, Ngoc-Ha, Apriletti, James W, Cunha Lima, Suzana T, Webb, Paul, Baxter, John D, Scanlan, Thomas S
• Format: Article
• Language: English
• Subjects: Acetates - chemical synthesis; Acetates - chemistry; Acetates - pharmacology; Binding, Competitive; Biological and medical sciences; DNA-Binding Proteins - agonists; DNA-Binding Proteins - metabolism; Drug Design; HeLa Cells; Hormones. Endocrine system; Humans; Medical sciences; Nuclear Proteins - metabolism; Nuclear Receptor Co-Repressor 1; Nuclear Receptor Coactivator 2; Pharmacology. Drug treatments; Phenoxyacetates; Radioligand Assay; Receptors, Cytoplasmic and Nuclear - agonists; Receptors, Cytoplasmic and Nuclear - metabolism; Receptors, Thyroid Hormone - agonists; Receptors, Thyroid Hormone - metabolism; Repressor Proteins - metabolism; Structure-Activity Relationship; Transcription Factors - metabolism; Transcriptional Activation; Triiodothyronine - antagonists & inhibitors
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0201013

Recent efforts have focused on the design and synthesis of thyroid hormone (T3) antagonists as potential therapeutic agents and chemical probes to understand hormone-signaling pathways. We previously reported the development of novel first-generation T3 antagonists DIBRT, HY-4, and GC-14 using the “extension hypothesis” as a general guideline in hormone antagonist design. − These compounds contain extensions at the 5‘-position (DIBRT, GC-14) of the outer thyronine ring or from the bridging carbon (HY-4). All of these compounds have only a modest affinity and potency for the thyroid hormone receptor (TR) that limits studies of their antagonistic actions. Here, we report the design and synthesis of a novel series of 5‘-phenylethynyl derivatives sharing the GC-1 halogen-free thyronine scaffold. One compound (NH-3) is a T3 antagonist with negligible TR agonist activity and improved TR binding affinity and potency that allow for further characterization of its observed activity. One mechanism for antagonism appears to be the ability of NH-3 to block TR−coactivator interactions. NH-3 will be a useful pharmacological tool for further study of T3 signaling and TR function.