Hammett analysis of selective thyroid hormone receptor modulators reveals structural and electronic requirements for hormone antagonists

Ngoc Ha Nguyen, James W. Apriletti, John D. Baxter, Thomas (Tom) Scanlan

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Selective thyroid hormone modulators that function as isoform-selective agonists or antagonists of the thyroid hormone receptors (TRs) might be therapeutically useful in diseases associated with aberrant hormone signaling. The most potent thyroid hormone antagonist reported to date is NH-3. To explore the significance of the 5′-p-nitroaryl moiety of NH-3 and understand what chemical features are important to confer antagonism, we sought to expand the structure-activity relationship data for the class of 5′-phenylethynyl GC-1 derivatives. Herein, we describe an improved synthetic route utilizing palladium-catalyzed chemistry for efficient access to a series of 5′-phenylethynyl compounds with varying size and electronic properties. We prepared and tested sixteen analogues for TR binding and transactivation activity. Substitution at the 5′-position decreased binding affinity, but retained TRβ-selectivity. In transactivation assays, the analogues displayed a spectrum of agonist, antagonist, and mixed agonist/antagonist activity that correlated with electronic character in a Hammett analysis between σ substituent value and TR modulation. Analogues NH-5, NH-7, NH-9, NH-11, and NH-23 displayed full antagonist activity with reduced potency compared to NH-3, indicating the nitro group is not required for antagonism. However, para-substitution with strong electron withdrawing properties on the 5′-aryl extension is important for antagonist activity, and antagonist potency-but not ligand receptor binding-was found to correlate linearly with the sigma values for the electron withdrawing substituents.

Original languageEnglish (US)
Pages (from-to)4599-4608
Number of pages10
JournalJournal of the American Chemical Society
Volume127
Issue number13
DOIs
StatePublished - Apr 6 2005
Externally publishedYes

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Hormone Antagonists
Thyroid Hormone Receptors
Hormones
Modulators
Thyroid Hormones
Transcriptional Activation
Substitution reactions
Electrons
Antithyroid Agents
Palladium
Structure-Activity Relationship
Electronic properties
Assays
Protein Isoforms
Ligands
Modulation
Derivatives

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

Hammett analysis of selective thyroid hormone receptor modulators reveals structural and electronic requirements for hormone antagonists. / Nguyen, Ngoc Ha; Apriletti, James W.; Baxter, John D.; Scanlan, Thomas (Tom).

In: Journal of the American Chemical Society, Vol. 127, No. 13, 06.04.2005, p. 4599-4608.

Research output: Contribution to journalArticle

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