Discovery of PH-797804, a highly selective and potent inhibitor of p38 MAP kinase

The synthesis and SAR studies of a novel N-aryl pyridinone class of p38 kinase inhibitors are described. Systematic structural modifications to the HTS lead, 5, led to the identification of (−)-4a as a clinical candidate for the treatment of inflammatory diseases. Additionally, the chiral synthesis...

Ausführliche Beschreibung

Gespeichert in:

Bibliographische Detailangaben
Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2011-07, Vol.21 (13), p.4066-4071
Hauptverfasser:	Selness, Shaun R, Devraj, Rajesh V, Devadas, Balekudru, Walker, John K, Boehm, Terri L, Durley, Richard C, Shieh, Huey, Xing, Li, Rucker, Paul V, Jerome, Kevin D, Benson, Alan G, Marrufo, Laura D, Madsen, Heather M, Hitchcock, Jeff, Owen, Tom J, Christie, Lance, Promo, Michele A, Hickory, Brian S, Alvira, Edgardo, Naing, Win, Blevis-Bal, Radhika, Messing, Dean, Yang, Jerry, Mao, Michael K, Yalamanchili, Gopi, Vonder Embse, Richard, Hirsch, Jeffrey, Saabye, Matthew, Bonar, Sheri, Webb, Elizabeth, Anderson, Gary, Monahan, Joseph B
Format:	Artikel
Sprache:	eng
Schlagworte:	Animals Benzamides - chemical synthesis Benzamides - chemistry Benzamides - pharmacology Biological and medical sciences Bones, joints and connective tissue. Antiinflammatory agents Disease Models, Animal Dogs Enzyme Activation - drug effects enzyme inhibitors Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Humans Inhibitory Concentration 50 Macaca fascicularis Male Medical sciences mitogen-activated protein kinase Molecular Structure p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors p38 Mitogen-Activated Protein Kinases - chemistry p38 Mitogen-Activated Protein Kinases - pharmacology Pharmacology. Drug treatments Pyridones Pyrones - chemical synthesis Pyrones - chemistry Pyrones - pharmacology Rats Rats, Sprague-Dawley Structure-Activity Relationship structure-activity relationships
Online-Zugang:	Volltext
Tags:	Tag hinzufügen Keine Tags, Fügen Sie den ersten Tag hinzu!

Beschreibung
Zusammenfassung:	The synthesis and SAR studies of a novel N-aryl pyridinone class of p38 kinase inhibitors are described. Systematic structural modifications to the HTS lead, 5, led to the identification of (−)-4a as a clinical candidate for the treatment of inflammatory diseases. Additionally, the chiral synthesis and properties of (−)-4a are described.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2011.04.121