Dissociated Nonsteroidal Glucocorticoid Receptor Modulators; Discovery of the Agonist Trigger in a Tetrahydronaphthalene−Benzoxazine Series
| Autor: | Melanie Washington, Davina Humphreys, Lesley Nisbet, Philip Alan Skone, Royston C. B. Copley, Simon J. F. Macdonald, Graham G. A. Inglis, Richard J. Upton, Mike D. Barker, Margaret Clackers, Victoria Vinader, Haydn Terence Jones, Michael John Johnston, Iain M. McLay, Derek A. Demaine, Stephen E. Shanahan, David House, Richard Loiseau, Dan Tape, Michael V. Haase, Francois Pacquet, Iain Uings |
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| Rok vydání: | 2006 |
| Předmět: |
Models
Molecular Transcriptional Activation Agonist medicine.medical_specialty Tetrahydronaphthalenes Transcription Genetic medicine.drug_class Administration Topical Binding Competitive Partial agonist Dexamethasone Cell Line Mice Radioligand Assay Structure-Activity Relationship Transactivation Receptors Glucocorticoid Glucocorticoid receptor Internal medicine Drug Discovery medicine Animals Humans Structure–activity relationship Hypersensitivity Delayed Receptor Transrepression Chemistry Anti-Inflammatory Agents Non-Steroidal Stereoisomerism Benzoxazines Endocrinology Docking (molecular) Molecular Medicine |
| Zdroj: | Journal of Medicinal Chemistry. 49:4216-4231 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | The tetrahydronaphthalene-benzoxazine glucocorticoid receptor (GR) partial agonist 4b was optimized to produce potent full agonists of GR. Aromatic ring substitution of the tetrahydronaphthalene leads to weak GR antagonists. Discovery of an "agonist trigger" substituent on the saturated ring of the tetrahydronaphthalene leads to increased potency and efficacious GR agonism. These compounds are efficacy selective in an NFkB GR agonist assay (representing transrepression effects) over an MMTV GR agonist assay (representing transactivation effects). 52 and 60 have NFkB pIC(50) = 8.92 (105%) and 8.69 (92%) and MMTV pEC(50) = 8.20 (47%) and 7.75 (39%), respectively. The impact of the trigger substituent on agonism is modeled within GR and discussed. 36, 52, and 60 have anti-inflammatory activity in a mouse model of inflammation after topical dosing with 52 and 60, having an effect similar to that of dexamethasone. The original lead was discovered by a manual agreement docking method, and automation of this method is also described. |
| Databáze: | OpenAIRE |
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