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Can I read Part 2: Structure–activity relationship (SAR) investigations of fused pyrazoles as potent, selective and orally available inhibitors of p38α mitogen-activated protein kinase on EtoBox?
Part 2: Structure–activity relationship (SAR) investigations of fused pyrazoles as potent, selective and orally available inhibitors of p38α mitogen-activated protein kinase by Ryan P. Wurz; Liping H. Pettus; Bradley Henkle; Lisa Sherman; Matthew Plant; Kent Miner; Helen J. McBride; Lu Min Wong; Christiaan J.M. Saris; Matthew R. Lee; Samer Chmait; Christopher Mohr; Faye Hsieh; Andrew S. Tasker is a Biochemistry, Genetics and Molecular Biology article available to read on EtoBox.
What is Part 2: Structure–activity relationship (SAR) investigations of fused pyrazoles as potent, selective and orally available inhibitors of p38α mitogen-activated protein kinase about?
A novel class of pyrazolopyridazine p38alpha mitogen-activated protein kinase (MAPK) inhibitors is disclosed. A structure activity relationship (SAR) investigation was conducted driven by the ability of these compounds to inhibit the p38alpha enzyme, the secretion of TNFalpha in a LPS-challenged THP1 cell line and TNFalpha-induced production of IL-8 in the presence of 50% human whole blood (hWB). This study resulted in the discovery of several inhibitors with IC(50) values in the single-digit nanomolar range in hWB. Further investigation of the pharmacokinetic profiles of these lead compounds led to the identification of three potent and orally bioavailable p38alpha inhibitors 2h, 2m, and 13h. Inhibitor 2m was found to be highly selective for p38alpha/beta over a panel of 402 other kinases in Ambit screening, and was highly efficacious in vivo in the inhibition of TNFalpha production in LPS-stimulated Lewis rats with an ED(50) of ca. 0.08mg/kg.
Who reads Part 2: Structure–activity relationship (SAR) investigations of fused pyrazoles as potent, selective and orally available inhibitors of p38α mitogen-activated protein kinase?
It is typically read by researchers, students, and practitioners in Biochemistry, Genetics and Molecular Biology.
- Author
- Ryan P. Wurz; Liping H. Pettus; Bradley Henkle; Lisa Sherman; Matthew Plant; Kent Miner; Helen J. McBride; Lu Min Wong; Christiaan J.M. Saris; Matthew R. Lee; Samer Chmait; Christopher Mohr; Faye Hsieh; Andrew S. Tasker
- Publisher
- Elsevier Science; Elsevier ; Elsevier Ltd.; Elsevier BV (ISSN 0960-894X)
- Published
- 2010
- Language
- EN
- Field
- Biochemistry, Genetics and Molecular Biology (Life Sciences)