Improvement of pharmacological properties of irreversible thyroid receptor coactivator binding inhibitors.

We have previously reported the discovery and preliminary structure activity relationships of a series of beta-aminoketones that disrupt the binding of coactivators to TR. However, the most active compounds had moderate inhibitory potency and relatively high cytotoxicity, resulting in narrow therapeutic index. Additionally, preliminary evaluation of in vivo toxicology revealed a significant dose related cardiotoxicity. Here we describe the improvement of pharmacological properties of thyroid hormone receptor coactivator binding inhibitors. A comprehensive survey of the effects of substitutents in key areas of the molecule was carried out based on mechanistic insight from the earlier report. This study revealed that both electron withdrawing and hydrophobic substituents on the aromatic ring led to higher potency. On the other hand, moving from an alkyl to a sulfonyl alkyl side chain led to reduced cytotoxicity. Finally, utilization of amine moieties having low pK(a)'s resulted in lowered ion channel activity without any loss of pharmacological activity.

[1]  B. Zhorov,et al.  Access and Binding of Local Anesthetics in the Closed Sodium Channel , 2008, Molecular Pharmacology.

[2]  R. Fletterick,et al.  Structural insight into the mode of action of a direct inhibitor of coregulator binding to the thyroid hormone receptor. , 2007, Molecular endocrinology.

[3]  Leann Nguyen,et al.  Is PAMPA a useful tool for discovery? , 2007, Journal of pharmaceutical sciences.

[4]  R. Fletterick,et al.  Inhibitors of the interaction of a thyroid hormone receptor and coactivators: preliminary structure-activity relationships. , 2007, Journal of medicinal chemistry.

[5]  L. Weidolf,et al.  Mimicry of phase I drug metabolism--novel methods for metabolite characterization and synthesis. , 2007, Rapid communications in mass spectrometry : RCM.

[6]  Manfred Kansy,et al.  High throughput solubility measurement in drug discovery and development. , 2007, Advanced drug delivery reviews.

[7]  J. Samarut,et al.  Thyroid hormones signaling is getting more complex: STORMs are coming. , 2007, Molecular endocrinology.

[8]  B. Pirotte,et al.  Design, synthesis, and pharmacological evaluation of R/S-3,4-dihydro-2,2-dimethyl- 6-halo-4-(phenylaminocarbonylamino)-2H-1-benzopyrans: toward tissue-selective pancreatic beta-cell KATP channel openers structurally related to (+/-)-cromakalim. , 2006, Journal of medicinal chemistry.

[9]  R. Fletterick,et al.  A High-Throughput Screening Method to Identify Small Molecule Inhibitors of Thyroid Hormone Receptor Coactivator Binding , 2006, Science's STKE.

[10]  R. Fletterick,et al.  Discovery of Small Molecule Inhibitors of the Interaction of the Thyroid Hormone Receptor with Transcriptional Coregulators* , 2005, Journal of Biological Chemistry.

[11]  Katherine A. Drake,et al.  Design and synthesis of complementing ligands for mutant thyroid hormone receptor TRβ(R320H): a tailor-made approach toward the treatment of resistance to thyroid hormone , 2005 .

[12]  Katherine A. Drake,et al.  Design and synthesis of complementing ligands for mutant thyroid hormone receptor TRbeta(R320H): a tailor-made approach toward the treatment of resistance to thyroid hormone. , 2005, Bioorganic & medicinal chemistry.

[13]  J. Malm.  Thyroid hormone ligands and metabolic diseases. , 2004, Current pharmaceutical design.

[14]  M. Machida,et al.  Biopharmaceutics Classification by High Throughput Solubility Assay and PAMPA , 2004, Drug development and industrial pharmacy.

[15]  G. Brent.  Tissue-Specific Actions of Thyroid Hormone: Insights From Animal Models , 2004, Reviews in Endocrine and Metabolic Disorders.

[16]  N. Leadbeater,et al.  Microwave-assisted Mannich-type three-component reactions , 2004, Molecular Diversity.

[17]  K. Luthman,et al.  Efficient large scale microwave assisted Mannich reactions using substituted acetophenones , 2004, Molecular Diversity.

[18]  S. N. Wright.  Cardiotoxic and antiarrhythmic tertiary amine local anesthetics: sodium channel affinity vs. sodium channel gating. , 2003, Current vascular pharmacology.

[19]  T. Scanlan,et al.  A Thyroid Hormone Antagonist That Inhibits Thyroid Hormone Action in Vivo * , 2002, The Journal of Biological Chemistry.

[20]  J. Baxter,et al.  Rational design and synthesis of a novel thyroid hormone antagonist that blocks coactivator recruitment. , 2002, Journal of medicinal chemistry.

[21]  P. Yen,et al.  Physiological and molecular basis of thyroid hormone action. , 2001, Physiological reviews.

[22]  Á. Pascual,et al.  Nuclear hormone receptors and gene expression. , 2001, Physiological reviews.

[23]  G. Williams,et al.  Cloning and Characterization of Two Novel Thyroid Hormone Receptor β Isoforms , 2000, Molecular and Cellular Biology.

[24]  H. Glatt,et al.  Benzylic hydroxylation of 1-methylpyrene and 1-ethylpyrene by human and rat cytochromes P450 individually expressed in V79 Chinese hamster cells. , 1999, Carcinogenesis.

[25]  R. Fletterick,et al.  Mechanisms of thyroid hormone action: insights from X-ray crystallographic and functional studies. , 1998, Recent progress in hormone research.

[26]  K. Umesono,et al.  The nuclear receptor superfamily: The second decade , 1995, Cell.

[27]  Corwin Hansch,et al.  A survey of Hammett substituent constants and resonance and field parameters , 1991 .

[28]  W. L. Nelson,et al.  Chemical aspects of metoprolol metabolism. Asymmetric synthesis and absolute configuration of the 3-[4-(1-hydroxy-2-methoxyethyl)phenoxy]-1-(isopropylamino)-2-propanols , the diastereomeric benzylic hydroxylation metabolites. , 1988, Journal of medicinal chemistry.

[29]  T. Tonoue,et al.  [Mechanism of thyroid hormone action]. , 1967, Saishin igaku. Modern medicine.