Discovery of a potent and dissociated non-steroidal glucocorticoid receptor agonist containing an alkyl carbinol pharmacophore
| Autor: | Donald Souza, Mark Panzenbeck, Jörg Bentzien, Tazmeen Fadra-Khan, Carol A. Torcellini, Roger M. Dinallo, Christian Harcken, Hossein Razavi, Alison Kukulka, Gerald Nabozny, Ljiljana Zuvela-Jelaska, David S. Thomson, Richard M. Nelson, Josephine Pelletier, Edward Pack, Doris Riether, John R. Proudfoot |
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| Rok vydání: | 2013 |
| Předmět: |
Agonist
Models Molecular medicine.drug_class Stereochemistry Prednisolone Clinical Biochemistry Anti-Inflammatory Agents Pharmaceutical Science Pharmacology Biochemistry Rats Sprague-Dawley Transactivation Inhibitory Concentration 50 Mice Mineralocorticoid receptor Glucocorticoid receptor Receptors Glucocorticoid Progesterone receptor Drug Discovery medicine Animals Humans Molecular Biology Glucocorticoids Transrepression Binding Sites Dose-Response Relationship Drug Molecular Structure Chemistry Arthritis Methanol Organic Chemistry Rats Disease Models Animal Nuclear receptor Molecular Medicine Pharmacophore Protein Binding |
| Zdroj: | Bioorganicmedicinal chemistry letters. 24(8) |
| ISSN: | 1464-3405 |
| Popis: | Synthesis and structure-activity relationship (SAR) of a series of alkyl and cycloalkyl containing non-steroidal dissociated glucocorticoid receptor (GR) agonists is reported. This series of compounds was identified as part of an effort to replace the CF3 group in a scaffold represented by 1a. The study culminated in the identification of compound 14, a t-butyl containing derivative, which has shown potent activity for GR, selectivity against the progesterone receptor (PR) and the mineralocorticoid receptor (MR), in vitro anti-inflammatory activity in an IL-6 transrepression assay, and dissociation in a MMTV transactivation counter-screen. In a collagen-induced arthritis mouse model, 14 displayed prednisolone-like efficacy, and lower impact on body fat and free fatty acids than prednisolone at an equivalent anti-inflammatory dose. |
| Databáze: | OpenAIRE |
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