Design and evaluation of novel 8-oxo-pyridopyrimidine Jak1/2 inhibitors

A highly ligand efficient, novel 8-oxo-pyridopyrimidine containing inhibitor of Jak1 and Jak2 isoforms with a pyridone moiety as the hinge-binding motif was discovered. Structure-based design strategies were applied to significantly improve enzyme potency and the polarity of the molecule was adjuste...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2013-11, Vol.23 (21), p.5923-5930
Hauptverfasser:	Labadie, Sharada, Barrett, Kathy, Blair, Wade S., Chang, Christine, Deshmukh, Gauri, Eigenbrot, Charles, Gibbons, Paul, Johnson, Adam, Kenny, Jane R., Kohli, Pawan Bir, Liimatta, Marya, Lupardus, Patrick J., Shia, Steven, Steffek, Micah, Ubhayakar, Savita, Abbema, Anne van, Zak, Mark
Format:	Artikel
Sprache:	eng
Schlagworte:	8-Oxo-pyridopyrimidines Crystal structure Hematopoiesis Humans JAK inhibitors Janus Kinase 1 - antagonists & inhibitors Janus Kinase 1 - chemistry Janus Kinase 1 - metabolism Janus Kinase 2 - antagonists & inhibitors Janus Kinase 2 - chemistry Janus Kinase 2 - metabolism Molecular Docking Simulation Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacology Pyrimidines - chemistry Pyrimidines - pharmacology Rheumatoid arthritis Structure-Activity Relationship
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Beschreibung
Zusammenfassung:	A highly ligand efficient, novel 8-oxo-pyridopyrimidine containing inhibitor of Jak1 and Jak2 isoforms with a pyridone moiety as the hinge-binding motif was discovered. Structure-based design strategies were applied to significantly improve enzyme potency and the polarity of the molecule was adjusted to gain cellular activity. The crystal structures of two representative inhibitors bound to Jak1 were obtained to enable SAR exploration.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2013.08.082