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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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2010-04, Vol.20 (8), p.2609-2613
Main Authors: 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: Article
Language:English
Subjects:
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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Summary: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