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

doi:10.1016/j.bmcl.2010.02.056

Bioorganic & Medicinal Chemistry Letters

Volume 20, Issue 8, 15 April 2010, Pages 2609-2613

https://doi.org/10.1016/j.bmcl.2010.02.056 Get rights and content

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.

Graphical abstract

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Thus, the combined techniques yielded potential drug candidates that may be further experimentally validated for the treatment of various autoimmune and inflammatory disorders. In the present study, diverse datasets of 99 (Table S1) and 211 (Table S2) (Supplementary information) inhibitor molecules for JAK1 and JAK3, respectively, were selected from the literature (Gerspacher et al., 2010; Pissot-Soldermann et al., 2010; Malerich et al., 2010; Schenkel et al., 2011; Thoma et al., 2010; Chen et al., 2006; Clark et al., 2007; Adams et al., 2003; Cole et al., 2009; Burns et al., 2009; Harikrishnan et al., 2011; Wilson et al., 2009; Lim et al., 2011; Derenzini et al., 2011; Pardanani et al., 2009; Williams et al., 2008). The reported IC50 values of a selected dataset of JAK1 inhibitors spanned over 0.0013-10.00 μM range of biological activity while the dataset of JAK3 inhibitors covers 0.0006-51.300 μM range of biological activity.
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Discovery and SAR of potent, orally available 2,8-diaryl-quinoxalines as a new class of JAK2 inhibitors

Abstract

Graphical abstract

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

Blood

Adv. Drug Delivery Rev.

Oncogene

Nat. Rev. Cancer