Design and synthesis of potent pyridazine inhibitors of p38 MAP kinase

Novel potent trisubstituted pyridazine inhibitors of p38 MAP (mitogen activated protein) kinase are described that have activity in both cell-based assays of cytokine release and animal models of rheumatoid arthritis. They demonstrated potent inhibition of LPS-induced TNF-α production in mice and ex...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2005-05, Vol.15 (9), p.2409-2413
Hauptverfasser:	Tamayo, Nuria, Liao, Lillian, Goldberg, Martin, Powers, David, Tudor, Yan-Yan, Yu, Violeta, Wong, Lu Min, Henkle, Bradley, Middleton, Scot, Syed, Rashid, Harvey, Timothy, Jang, Graham, Hungate, Randall, Dominguez, Celia
Format:	Artikel
Sprache:	eng
Schlagworte:	Binding Sites Biological and medical sciences Bones, joints and connective tissue. Antiinflammatory agents Drug Design Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - pharmacology Humans Indicators and Reagents Kinetics Medical sciences Microsomes, Liver - enzymology Models, Molecular Molecular Structure p38 Kinase inhibitors p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors p38 Mitogen-Activated Protein Kinases - chemistry Pharmacology. Drug treatments Protein Conformation Pyridazines Pyridazines - chemical synthesis Pyridazines - pharmacology Structure-Activity Relationship
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Zusammenfassung:	Novel potent trisubstituted pyridazine inhibitors of p38 MAP (mitogen activated protein) kinase are described that have activity in both cell-based assays of cytokine release and animal models of rheumatoid arthritis. They demonstrated potent inhibition of LPS-induced TNF-α production in mice and exhibited good efficacy in the rat collagen induced arthritis model. Novel potent trisubstituted pyridazine inhibitors of p38 MAP (mitogen activated protein) kinase are described that have activity in both cell-based assays of cytokine release and animal models of rheumatoid arthritis. They demonstrated potent inhibition of LPS-induced TNF-α production in mice and exhibited good efficacy in the rat collagen induced arthritis model.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2005.02.010