Structure Guided Design of 5-Arylindazole Glucocorticoid Receptor Agonists and Antagonists
| Autor: | Robert J. H. Austin, Christopher Patten, Eugene L. Stewart, Simon Taylor, Peter Brown, Christopher M. Yates, Davina C. Angell, Jason A. Holt, Rosemary Z. Sasse, Iain Uings, Ryan P. Trump, Jodi M. Maglich |
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| Rok vydání: | 2010 |
| Předmět: |
Male
Models Molecular Agonist medicine.medical_specialty Indazoles Protein Conformation medicine.drug_class Pharmacology Substrate Specificity Mice Receptors Glucocorticoid Therapeutic index Glucocorticoid receptor In vivo Internal medicine Drug Discovery Glucocorticoid Receptor Agonists medicine Animals Humans Dose-Response Relationship Drug Chemistry NF-kappa B Fibroblasts NFKB1 In vitro Rats Endocrinology Docking (molecular) Drug Design Molecular Medicine |
| Zdroj: | Journal of Medicinal Chemistry. 53:4531-4544 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | Glucocorticoid receptor (GR) agonists have been used for more than half a century as the most effective treatment of acute and chronic inflammatory conditions despite serious side effects that accompany their extended use that include glucose intolerance, muscle wasting, skin thinning, and osteoporosis. As a starting point for the identification of GR ligands with an improved therapeutic index, we wished to discover selective nonsteroidal GR agonists and antagonists with simplified structure compared to known GR ligands to serve as starting points for the optimization of dissociated GR modulators. To do so, we selected multiple chemical series by structure guided docking studies and evaluated GR agonist activity. From these efforts we identified 5-arylindazole compounds that showed moderate binding to the glucocorticoid receptor (GR) with clear opportunities for further development. Structure guided optimization was used to design arrays that led to potent GR agonists and antagonists. Several in vitro and in vivo experiments were utilized to demonstrate that GR agonist 23a (GSK9027) had a profile similar to that of a classical steroidal GR agonist. |
| Databáze: | OpenAIRE |
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