Rational design and synthesis of a novel thyroid hormone antagonist that blocks coactivator recruitment

Ngoc Ha Nguyen, James W. Apriletti, Suzana T. Cunha Lima, Paul Webb, John D. Baxter, Thomas (Tom) Scanlan

Research output: Contribution to journalArticle

90 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3310-3320
Number of pages11
JournalJournal of Medicinal Chemistry
Volume45
Issue number15
DOIs
StatePublished - Jul 18 2002
Externally publishedYes

Fingerprint

Hormone Antagonists
Antithyroid Agents
Thyroid Hormone Receptors
Thyroid Hormones
Thyronines
Hormones
Halogens
Triiodothyronine
Scaffolds
Carbon
Pharmacology
Guidelines
Derivatives

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Rational design and synthesis of a novel thyroid hormone antagonist that blocks coactivator recruitment. / Nguyen, Ngoc Ha; Apriletti, James W.; Cunha Lima, Suzana T.; Webb, Paul; Baxter, John D.; Scanlan, Thomas (Tom).

In: Journal of Medicinal Chemistry, Vol. 45, No. 15, 18.07.2002, p. 3310-3320.

Research output: Contribution to journalArticle

Nguyen, Ngoc Ha ; Apriletti, James W. ; Cunha Lima, Suzana T. ; Webb, Paul ; Baxter, John D. ; Scanlan, Thomas (Tom). / Rational design and synthesis of a novel thyroid hormone antagonist that blocks coactivator recruitment. In: Journal of Medicinal Chemistry. 2002 ; Vol. 45, No. 15. pp. 3310-3320.
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