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

Carole Pissot-Soldermann; Marc Gerspacher; Pascal Furet; Christoph Gaul; Philipp Holzer; Clive McCarthy; Thomas Radimerski; Catherine H Regnier; Fabienne Baffert; Peter Drueckes; Gisele A Tavares; Eric Vangrevelinghe; Francesca Blasco; Giorgio Ottaviani; Flavio Ossola; Julien Scesa; Janitha Reetz

doi:10.1016/j.bmcl.2010.02.056

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

Bioorg Med Chem Lett. 2010 Apr 15;20(8):2609-13. doi: 10.1016/j.bmcl.2010.02.056. Epub 2010 Feb 19.

Authors

Carole Pissot-Soldermann¹, Marc Gerspacher, Pascal Furet, Christoph Gaul, Philipp Holzer, Clive McCarthy, Thomas Radimerski, Catherine H Regnier, Fabienne Baffert, Peter Drueckes, Gisele A Tavares, Eric Vangrevelinghe, Francesca Blasco, Giorgio Ottaviani, Flavio Ossola, Julien Scesa, Janitha Reetz

Affiliation

¹ Novartis Institutes for Biomedical Research, Novartis Pharma AG, WKL-136.4.96, CH-4002 Basel, Switzerland. [email protected]

PMID: 20231096
DOI: 10.1016/j.bmcl.2010.02.056

Abstract

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.

MeSH terms

Administration, Oral
Animals
Cell Line
Drug Discovery
Drug Evaluation, Preclinical
Janus Kinase 2 / antagonists & inhibitors*
Models, Molecular
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacokinetics
Protein Kinase Inhibitors / pharmacology*
Quinoxalines / chemistry*
Quinoxalines / pharmacokinetics
Quinoxalines / pharmacology*
Rats
Structure-Activity Relationship

Substances

Protein Kinase Inhibitors
Quinoxalines
Jak2 protein, rat
Janus Kinase 2