Discovery and SAR of potent, orally available 2,8-diaryl-quinoxalines as a new class of JAK2 inhibitors

We have designed and synthesized a novel series of 2,8-diaryl-quinoxalines as Janus kinase 2 inhibitors. Many of the inhibitors show low nanomolar activity against JAK2 and potently suppress proliferation of SET-2 cells in vitro. In addition, compounds from this series have favorable rat pharmacokin...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2010-04, Vol.20 (8), p.2609-2613
Hauptverfasser:	Pissot-Soldermann, Carole, Gerspacher, Marc, Furet, Pascal, Gaul, Christoph, Holzer, Philipp, McCarthy, Clive, Radimerski, Thomas, Regnier, Catherine H., Baffert, Fabienne, Drueckes, Peter, Tavares, Gisele A., Vangrevelinghe, Eric, Blasco, Francesca, Ottaviani, Giorgio, Ossola, Flavio, Scesa, Julien, Reetz, Janitha
Format:	Artikel
Sprache:	eng
Schlagworte:	Administration, Oral Animals Antineoplastic agents Biological and medical sciences Cell Line Drug Discovery Drug Evaluation, Preclinical General aspects JAK1 JAK2 JAK3 Janus kinase Janus Kinase 2 - antagonists & inhibitors Kinase inhibitors Medical sciences Models, Molecular Pharmacology. Drug treatments Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacokinetics Protein Kinase Inhibitors - pharmacology Quinoxalines - chemistry Quinoxalines - pharmacokinetics Quinoxalines - pharmacology Rats Structure-Activity Relationship Tyk2
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Beschreibung
Zusammenfassung:	We have designed and synthesized a novel series of 2,8-diaryl-quinoxalines as Janus kinase 2 inhibitors. Many of the inhibitors show low nanomolar activity against JAK2 and potently suppress proliferation of SET-2 cells in vitro. In addition, compounds from this series have favorable rat pharmacokinetic properties suitable for in vivo efficacy evaluation.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2010.02.056