Design, Synthesis, and Structure−Activity Relationships of Aminopyridine N-Oxides, a Novel Scaffold for the Potent and Selective Inhibition of p38 Mitogen Activated Protein Kinase
| العنوان: | Design, Synthesis, and Structure−Activity Relationships of Aminopyridine N-Oxides, a Novel Scaffold for the Potent and Selective Inhibition of p38 Mitogen Activated Protein Kinase |
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| المؤلفون: | María Domínguez, Laura Vidal, Wenceslao Lumeras, Nuria Godessart, Adelina Orellana, Cristina Balagué, Cristina Esteve, Ramón Roca, Bernat Vidal, Francisco Caturla, Josep M. Huerta |
| المصدر: | Journal of Medicinal Chemistry. 52:5531-5545 |
| بيانات النشر: | American Chemical Society (ACS), 2009. |
| سنة النشر: | 2009 |
| مصطلحات موضوعية: | Male, Models, Molecular, Aminopyridines, Pharmacology, p38 Mitogen-Activated Protein Kinases, Cell Line, Substrate Specificity, Inhibitory Concentration 50, Structure-Activity Relationship, In vivo, Oral administration, Catalytic Domain, Drug Discovery, Animals, Humans, Potency, Rats, Wistar, Protein Kinase Inhibitors, Whole blood, biology, Tumor Necrosis Factor-alpha, Kinase, Chemistry, Oxides, Arthritis, Experimental, In vitro, Rats, Biochemistry, Enzyme inhibitor, Drug Design, Mitogen-activated protein kinase, biology.protein, Molecular Medicine |
| الوصف: | A novel series of aminopyridine N-oxides were designed, synthesized, and tested for their ability to inhibit p38alpha MAP kinase. Some of these compounds showed a significant reduction in the LPS-induced TNFalpha production in human whole blood. Structure-activity relationship studies revealed that N-oxide oxygen was essential for activity and was probably a determinant factor for a marked selectivity against other related kinases. Compound 45 was identified as a potent and selective p38alpha inhibitor with an appropriate balance between potency and pharmacokinetics. In vivo efficacy of 45 was demonstrated in reducing TNFalpha levels in an acute murine model of inflammation (ED(50) = 1 mg/kg in LPS-induced TNFalpha production when dosed orally 1.5 h prior to LPS administration). The oral efficacy of 45 was further demonstrated in a chronic model of adjuvant arthritis in rats with established disease when administered orally (ED(50) = 4.5 mg/kg). |
| تدمد: | 1520-4804 0022-2623 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b495cfd7a1b917e7dc4356e7516bb008 https://doi.org/10.1021/jm9008604 |
| رقم الأكسشن: | edsair.doi.dedup.....b495cfd7a1b917e7dc4356e7516bb008 |
| قاعدة البيانات: | OpenAIRE |
Find this issue from the American Chemical Society | تدمد: | 15204804 00222623 |
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