Nonsteroidal Selective Glucocorticoid Modulators: The Effect of C-10 Substitution on Receptor Selectivity and Functional Potency of 5-Allyl-2,5-dihydro-2,2,4-trimethyl-1H-[1]benzopyrano[3,4-f]quinolines
| العنوان: | Nonsteroidal Selective Glucocorticoid Modulators: The Effect of C-10 Substitution on Receptor Selectivity and Functional Potency of 5-Allyl-2,5-dihydro-2,2,4-trimethyl-1H-[1]benzopyrano[3,4-f]quinolines |
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| المؤلفون: | Jeffery N. Miner, Chun W. Lin, Michael A. Stashko, Peer B. Jacobson, Masake Nakane, Philip R. Kym, Daniel P. Larson, Steven W. Elmore, H. Douglass Falls, Michael J. Coghlan, Loan N. Miller, Curtis M. Tyree, Jimmie L. Moore, Denise Wilcox, Rui Tang, Michael E. Kort, Benjamin C. Lane, Phong Nguyen, James D. Ratajczyk, John K. Pratt |
| المصدر: | Journal of Medicinal Chemistry. 46:1016-1030 |
| بيانات النشر: | American Chemical Society (ACS), 2003. |
| سنة النشر: | 2003 |
| مصطلحات موضوعية: | Transcription, Genetic, Stereochemistry, T-Lymphocytes, medicine.medical_treatment, In Vitro Techniques, Carrageenan, Ligands, Response Elements, Binding, Competitive, Chemical synthesis, Steroid, Rats, Sprague-Dawley, Structure-Activity Relationship, Receptors, Glucocorticoid, Glucocorticoid receptor, Species Specificity, Drug Discovery, Concanavalin A, medicine, Animals, Edema, Humans, Protein Isoforms, Potency, Receptor, Reporter gene, Chemistry, Anti-Inflammatory Agents, Non-Steroidal, NF-kappa B, Rats, Allyl Compounds, Transcription Factor AP-1, Quinolines, Prednisolone, Molecular Medicine, E-Selectin, Cell Division, Glucocorticoid, medicine.drug |
| الوصف: | The preparation and characterization of a series of C-10 substituted 5-allyl-2,5-dihydro-2,2,4-trimethyl-1H-[1]benzopyrano[3,4-f]quinolines as a novel class of selective ligands for the glucocorticoid receptor is described. Substitution at the C-10 position of the tetracyclic core with linear, two-atom appendages (OCH(3), OCF(2)H, NHMe, SMe, CH=CH(2), Ctbd1;CH, CH(2)OH) provided molecules of high affinity (K(i) = 2-8 nM) for the human glucocorticoid receptor (hGR) with limited cross-reactivity with other steroid receptors (PR, MR, AR, ER). Optimal analogues showed slightly less potent but highly efficacious E-selectin repression with reduced levels of GRE activation efficacy in reporter gene assays relative to prednisolone. Preliminary SAR of analogues containing substitution at the C-9 and C-10 positions identified the 9-OH, 10-OMe analogue 50 and the 9-OH, 10-Cl analogue 58 as compounds that demonstrated potent, GR-mediated inhibition in a conconavalin A stimulated T-cell proliferation assay in both rodent and human whole blood monocytes. When evaluated for their in vivo effects in carrageenan-induced paw edema in rats, 50, 58, and 10-OCF(2)H analogue 35 showed dose-dependent anti-inflammatory effects (50, ED(50) = 16 mg/kg; 58, ED(50) = 15 mg/kg; 35, ED(50) = 21 mg/kg vs ED(50) = 15 mg/kg for 18 and ED(50) = 4 mg/kg for prednisolone). |
| تدمد: | 1520-4804 0022-2623 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2d3260ef0df0e55a15e67ec5aae902de https://doi.org/10.1021/jm020335m |
| رقم الأكسشن: | edsair.doi.dedup.....2d3260ef0df0e55a15e67ec5aae902de |
| قاعدة البيانات: | OpenAIRE |
Find this issue from the American Chemical Society | تدمد: | 15204804 00222623 |
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