Novel heterocyclic thyromimetics

• Published in: Bioorganic & medicinal chemistry letters Vol. 15; no. 7; pp. 1835 - 1840
• Main Authors: Haning, Helmut, Woltering, Michael, Mueller, Ulrich, Schmidt, Gunter, Schmeck, Carsten, Voehringer, Verena, Kretschmer, Axel, Pernerstorfer, Josef
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.04.2005; Elsevier
• Subjects: Animals; Binding Sites; Biological and medical sciences; Biological Assay; Heterocyclic Compounds - chemical synthesis; Heterocyclic Compounds - pharmacology; Hormones. Endocrine system; Indazoles; Indazoles - chemistry; Indoles; Indoles - chemistry; Ligands; Medical sciences; Molecular Mimicry; Pharmacology. Drug treatments; Phenols - chemistry; Receptors, Thyroid Hormone - agonists; Structure-Activity Relationship; Thyromimetics; Transfection; Triiodothyronine - pharmacology; Thyromimetics; Indazoles; Indoles; Mimetic hormone; Agonist; Molecular form; Nitrogen heterocycle; Selectivity; In vitro; Indazole derivatives; Structure activity relation; Bicyclic compound; Affinity; Carboxamide; Thyroid hormone; Aromatic compound; Indole derivatives; Chemical synthesis; Hormonal receptor
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2005.02.028

The synthesis of novel heterocycle containing thyromimetics is reported. Potent indole thyromimetics are presented (e.g., 8) that show a 10-fold selectivity in activation of THRβ over THRα. Novel heterocycle-fused thyromimetics are presented carrying indoles or indazoles instead of the phenolic group in T3. Potent agonists were identified in both series. SAR trends are examined and found to be mostly consistent with previously published thyromimetics. Moderate THRβ selectivity (approx. 10-fold) was observed in the indole series using isoform-selective transient THR transfection assays