Thyroid receptor ligands. Part 2: Thyromimetics with improved selectivity for the thyroid hormone receptor beta
| Autor: | Konrad F. Koehler, Todd J. Friends, Marlena Grynfarb, Pratik Devasthale, Arthur M. Doweyko, Bolette Husman, Howard Einspahr, Jon J. Hangeland, John S. Sack, Tamara Dejneka, Jan Ljunggren, Cheryl M. Sheppard, Karin Mellström, Johnny Sandberg, Denis E. Ryono, Mathias Färnegårdh, Johan Malm |
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| Rok vydání: | 2004 |
| Předmět: |
Agonist
Steric effects Thyroid Hormones medicine.drug_class Stereochemistry Clinical Biochemistry Pharmaceutical Science Crystallography X-Ray Ligands Biochemistry Cell Line Thyroid hormone receptor beta 2-Propanol chemistry.chemical_compound Inhibitory Concentration 50 Structure-Activity Relationship Amide Drug Discovery medicine Side chain Moiety Structure–activity relationship Amino Acids Molecular Biology Thyroid hormone receptor Binding Sites Chemistry Organic Chemistry Thyroid Hormone Receptors beta Drug Design Molecular Medicine Triiodothyronine |
| Zdroj: | Bioorganicmedicinal chemistry letters. 14(13) |
| ISSN: | 0960-894X |
| Popis: | A set of thyromimetics having improved selectivity for TR-beta1 were prepared by replacing the 3'-isopropyl group of 2 and 3 with substituents having increased steric bulk. From this limited SAR study, the most potent and selective compounds identified were derived from 2 and contained a 3'-phenyl moiety bearing small hydrophobic groups meta to the biphenyl link. X-ray crystal data of 15c complexed with TR-beta1 LBD shows methionine 442 to be displaced by the bulky R3' phenyl ethyl amide side chain. Movement of this amino acid side chain provides an expanded pocket for the bulky side chain while the ligand-receptor complex retains full agonist activity. |
| Databáze: | OpenAIRE |
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